Anti-FGFR3 antibodies and antigen binding fragments and methods of use thereof

Abstract

The present invention provides antibodies that specifically bind to FGFR3 and methods for treating or preventing cancer, such as bladder cancer.

Description

[0001] Cross - Reference to Related Applications

[0002] This application claims priority to U.S. Provisional Application No. 63 / 383,686, filed on November 14, 2022, and U.S. Provisional Application No. 63 / 587,538, filed on October 3, 2023, the disclosures of both of which are hereby incorporated by reference in their entireties.

[0003] Sequence Listing

[0004] This application contains a sequence listing that has been submitted electronically in XML file format and is hereby incorporated by reference in its entirety. The XML copy, created on November 3, 2023, is named 250298_000563_SL.xml and is 265,438 bytes in size. Technical Field

[0005] The present invention relates to antibodies and antigen-binding fragments thereof that specifically bind to FGFR3 and methods for treating disorders such as cancer. Background Art

[0006] Several cancer genome profiling studies have identified FGFR3 as a common mutation unique to non-inflammatory bladder tumors. FGFR3 mutations, including fusions, are enriched in the luminal papillary (LumP) subtype of MIBC (30% to 40%), which is characterized by low immune cell infiltration.

[0007] CD73 or ecto-5'-nucleotidase (ecto-5'-NT, EC 3.1.3.5) is a cell surface enzyme that catalyzes the dephosphorylation of extracellular AMP to adenosine. It is widely expressed in many types of cancer and has been associated with a pro-metastatic phenotype in melanoma and breast cancer. Adenosine activates an immunoregulatory response through specific receptors that protects tissues from damage caused by excessive inflammation. Extracellular adenosine levels remain low under physiological conditions, but they increase during inflammation and cell death. In T cells, the high-affinity adenosine receptor A2A (A2AR) is activated by adenosine to increase cytoplasmic cyclic AMP levels. This inhibits T cell functions such as proliferation and cytokine secretion.

[0008] Erdafitinib is a pan-FGFR tyrosine kinase inhibitor (TKI) approved for the treatment of bladder cancer with FGFR3 alterations. The rapidly increasing number of resistance mutations and toxicities associated with TKIs (hyperphosphatemia, ocular toxicity) pose a challenge to the treatment of cancer by targeting FGFR3. In addition, the antibody B-701 (Volvantuzumab) has been studied for the treatment of metastatic urothelial carcinoma (MUCC) and as a targeted alpha therapy. Necchi et al., The Journal of Urology, Vol. 201, Suppl. 4S, 2019, e840, abstract: PD47-08; Storozhuk et al., FGFR3 Targeted Alpha Therapeutic 225 AC]-FPI-1966 Induces Regression in Preclinical Bladder Xenograft Model (Fusion Pharmaceuticals, Inc. (2020)). Summary of the Invention

[0009] The present invention provides: an isolated antibody or antigen-binding fragment thereof that specifically binds to FGFR3 (e.g., monomeric or dimeric FGFR3b; optionally, with the proviso that FGFR3 is not FGFR3c) or an antigenic fragment thereof (optionally in combination with an additional therapeutic agent, such as, for example, a FGFR inhibitor, erdafitinib, pemitinib, infigratinib, rogatinib, dexamethasone, an alkylating drug, altretinoin, trabectedin or busulfan, nitrosoureas, carmustine, lomustine, a cytotoxic antibiotic, an anthracycline, doxorubicin, valrubicin, bleomycin or dactinomycin, an antimetabolite, methotrexate, fluorouracil, glycosides, clofarabine, pralatrexate, vinca alkaloids, vinblastine, vinorelbine, vincristine, vindesine, photodynamic drugs, porfimer sodium, aminolevulinic acid, platinum drugs, cisplatin, phenanthriplatin, taxanes, paclitaxel, docetaxel, topoisomerase inhibitors, irinotecan, topotecan, etoposide, teniposide, ziv-aflibercept, anticancer antibodies, rituximab, trastuzumab, cetuximab, cemiplizumab, pembrolizumab, panitumumab and bevacizumab), the isolated antibody or antigen-binding fragment thereof comprising: a heavy chain variable region (HCVR) comprising SEQ: SEQ ID NO: 2, 22, 42, 62, 82, 102, 122, 140, 159, 169, 179, 199 or 219, and a light chain variable region (LCVR) comprising a LCDR1, LCDR2, and LCDR3 of a LCVR comprising the amino acid sequence set forth in SEQ ID NO: 10, 30, 50, 70, 90, 110, 130, 148, 187, 207 or 227; or an isolated antibody or antigen-binding fragment thereof that specifically binds to FGFR3 as such an antibody or fragment, or competes with such an antibody or fragment for binding to FGFR3. In one embodiment of the invention, the antibody or antigen-binding fragment comprises: (a) a heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of a HCVR comprising the amino acid sequence set forth in SEQ ID NO: 2, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of a LCVR comprising the amino acid sequence set forth in SEQ ID NO: 10, (b) a heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of a HCVR comprising the amino acid sequence set forth in SEQ ID NO: 22, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of a LCVR comprising the amino acid sequence set forth in SEQ ID NO: 30,(c) a heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of a HCVR comprising the amino acid sequence set forth in SEQ ID NO:42, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of a LCVR comprising the amino acid sequence set forth in SEQ ID NO:50, (d) a heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of a HCVR comprising the amino acid sequence set forth in SEQ ID NO:62, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of a LCVR comprising the amino acid sequence set forth in SEQ ID NO:70, (e) a heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of a HCVR comprising the amino acid sequence set forth in SEQ ID NO:82, and a light chain variable region (LCVR) comprising NO: 90, (f) a heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of a HCVR comprising the amino acid sequence set forth in SEQ ID NO: 102, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of a LCVR comprising the amino acid sequence set forth in SEQ ID NO: 110, and / or (g) a heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of a HCVR comprising the amino acid sequence set forth in SEQ ID NO: 122, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of a LCVR comprising the amino acid sequence set forth in SEQ ID NO: 130, (h) a heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of a HCVR comprising the amino acid sequence set forth in SEQ ID NO: NO: 140, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of a LCVR comprising the amino acid sequence set forth in SEQ ID NO: 148, (i) a heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of a HCVR comprising the amino acid sequence set forth in SEQ ID NO: 159, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of a LCVR comprising the amino acid sequence set forth in SEQ ID NO: 148,(j) a heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of a HCVR comprising the amino acid sequence set forth in SEQ ID NO: 169, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of a LCVR comprising the amino acid sequence set forth in SEQ ID NO: 148, (k) a heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of a HCVR comprising the amino acid sequence set forth in SEQ ID NO: 179, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of a LCVR comprising the amino acid sequence set forth in SEQ ID NO: 187, (l) a heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of a HCVR comprising the amino acid sequence set forth in SEQ ID NO: 199, and a light chain variable region (LCVR) comprising SEQ ID NO: 207, and / or (m) a heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of a HCVR comprising the amino acid sequence set forth in SEQ ID NO: 219, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of a LCVR comprising the amino acid sequence set forth in SEQ ID NO: 227. In one embodiment of the present invention, the antibody or antigen-binding fragment comprises: (a) a heavy chain variable region comprising a HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 4, a HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 6, and a HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 8, and a light chain variable region comprising a LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 16; (b) a heavy chain variable region comprising a HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 24, a HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 26, and a HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 28,and a light chain variable region comprising a LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 32, a LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 34, and a LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 36; (c) a heavy chain variable region comprising a HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 44, a HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 46, and a HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 48, and a light chain variable region comprising a LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 52, a LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 54, and a LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 56; (d) a heavy chain variable region comprising a HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 64, a HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 66, and a HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: NO: 68, and a light chain variable region comprising: a LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 72, a LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 74, and a LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 76; (e) a heavy chain variable region comprising: a HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 84, a HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 86, and a HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 88, and a light chain variable region comprising: a LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 92, a LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 94, and a LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 96; (f) a heavy chain variable region comprising: a HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 104, a LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 106, and a LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 110. HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 106 and HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 108,and a light chain variable region comprising a LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 112, a LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 114, and a LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 116; (g) a heavy chain variable region comprising a HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 124, a HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 126, and a HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 128, and a light chain variable region comprising a LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 132, a LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 34, and a LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 134; (h) a heavy chain variable region comprising a HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 142, a HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 144, and a HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: NO: 146, and a light chain variable region comprising: a LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 150, a LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 153; (i) a heavy chain variable region comprising: a HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 161, a HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 163, and a HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 165, and a light chain variable region comprising: a LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 150, a LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 153; (j) a heavy chain variable region comprising: a HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 171, a LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 173, and a HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 175. HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 173 and HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 175,and a light chain variable region comprising a LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 150, a LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 153; (k) a heavy chain variable region comprising a HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 181, a HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 183, and a HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 185, and a light chain variable region comprising a LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 189, a LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 191, and a LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 193; (l) a heavy chain variable region comprising a HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 201, a HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 203, and a HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: NO: 205, and a light chain variable region comprising a LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 209, a LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 211, and a LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 213; and / or (m) a heavy chain variable region comprising a HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 221, a HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 223, and a HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 225, and a light chain variable region comprising a LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 32, a LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 34, and a LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 76. In one embodiment of the present invention, the antibody or antigen-binding fragment comprises: a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 2, 22, 42, 62, 82, 102, 122, 140, 159, 169, 179, 199 or 219, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 10, 30, 50, 70, 90, 110, 130, 148, 187, 207 or 227. In one embodiment of the present invention, the antibody or antigen-binding fragment comprises: (a) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 2,and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 10; (b) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 22, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 30; (c) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 42, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 50; (d) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 62, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 70; (e) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 82, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 90; (f) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 102, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 110; (g) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 1 NO: 122, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 130; (h) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 140, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 148; (i) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 159, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 148; (j) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 169, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 148; (k) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 179, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 187; (l) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 199, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: NO: 207; and / or (m) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 219, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 227. In one embodiment of the present invention, the antibody or antigen-binding fragment comprises: (a) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 18, 38, 58, 78, 98, 118, 136, 155, 167, 177, 195, 215 or 229, and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 20, 40, 60, 80, 100, 120, 138, 157, 197, 217, 231; for example,It comprises: (a) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 18, and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 20; (b) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 38, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 40; (c) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 58, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 60; (d) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 78, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 80; (e) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 98, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 100; (f) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 118, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: (g) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 136, and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 138; (h) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 155, and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 157; (i) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 167, and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 157; (j) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 177, and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 157; (k) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 195, and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 197; (l) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 215, and a light chain comprising the amino acid sequence set forth in SEQ ID NO: NO: 217; and / or (m) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 229, and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 231. In one embodiment of the present invention, the antibody or antigen-binding fragment thereof binds to one or more FGFR3 epitopes selected from the group consisting of: a. an epitope comprising the sequence GPTVWVK (SEQ ID NO: 260), and / or an epitope comprising the sequence TQR; b. an epitope comprising the sequence ADVR (SEQ ID NO: 258), and / or an epitope comprising the sequence IGVAEK (SEQ ID NO: 259); c. an epitope comprising the sequence HCKVY (SEQ ID NO: 261),and / or an epitope comprising the sequence KSWISE (SEQ ID NO:262), and / or an epitope comprising the sequence ADVR (SEQ ID NO:263); e. an epitope comprised within or overlapping with the sequence GPTVWVK (SEQ ID NO:260), and / or an epitope comprised within or overlapping with the sequence TQR; f. an epitope comprised within or overlapping with the sequence ADVR (SEQ ID NO:258), and / or an epitope comprised within or overlapping with the sequence IGVAEK (SEQ ID NO:259); and g. an epitope comprised within or overlapping with the sequence HCKVY (SEQ ID NO:261), and / or an epitope comprised within or overlapping with the sequence KSWISE (SEQ ID NO:262), and / or an epitope comprised within or overlapping with the sequence ADVR (SEQ ID NO:263). In one embodiment of the present invention, the antibody or antigen-binding fragment thereof binds to one or more FGFR3 epitopes selected from the group consisting of: a. an epitope consisting of the sequence GPTVWVK (SEQ ID NO: 260), and / or an epitope consisting of the sequence IGVAEK (SEQ ID NO: 259); b. an epitope consisting of the sequence ADVR (SEQ ID NO: 258), and / or an epitope consisting of the sequence IGVAEK (SEQ ID NO: 259); and c. an epitope consisting of the sequence HCKVY (SEQ ID NO: 261), and / or an epitope consisting of the sequence KSWISE (SEQ ID NO: 262), and / or an epitope consisting of the sequence ADVR (SEQ ID NO: 263). In one embodiment of the present invention, the antibody or antigen-binding fragment thereof binds to one or more FGFR3 epitopes selected from the following: a. an epitope comprising the sequence SCPPPGGGPMGPTVWVKDGTGLVPSER (SEQ ID NO: 245), and / or an epitope comprising the sequence YSCRQRLTQRVL (SEQ ID NO: 246); b. an epitope comprising the sequence LLAVPAAN (SEQ ID NO: 247), and / or an epitope comprising the sequence VLERSPHRPILQAG (SEQ ID NO: 248), and / or an epitope comprising the sequence YVTVLKSWISE (SEQ ID NO: 249), and / or an epitope comprising the sequence ADVRLR (SEQ ID NO: 250), and / or an epitope comprising the sequence LCRATNFIGVAEKAFW (SEQ ID NO: 251); c. an epitope comprising the sequence GQQEQLVFGSGDAVE (SEQ ID NO: 252),and / or an epitope comprising the sequence VLVGPQRL (SEQ ID NO: 253); d. an epitope comprising the sequence VLERSPHRPILQAG (SEQ ID NO: 254), and / or an epitope comprising the sequence HCKVYSDAQP (SEQ ID NO: 255), and / or an epitope comprising the sequence YVTVLKSWISESVEADVRLR (SEQ ID NO: 256), and / or an epitope comprising the sequence LCRATNFIGVAEKAF (SEQ ID NO: 257); e. an epitope contained within or overlapping with the sequence SCPPPGGGPMGPTVWVKDGTGLVPSER (SEQ ID NO: 245), and / or an epitope contained within or overlapping with the sequence YSCRQRLTQRVL (SEQ ID NO: 246); f. an epitope contained within or overlapping with the sequence LLAVPAAN (SEQ ID NO: 257). NO:247), and / or an epitope contained within or overlapping with the sequence VLERSPHRPILQAG (SEQ ID NO:248), and / or an epitope contained within or overlapping with the sequence YVTVLKSWISE (SEQ ID NO:249), and / or an epitope contained within or overlapping with the sequence ADVRLR (SEQ ID NO:250), and / or an epitope contained within or overlapping with the sequence LCRATNFIGVAEKAFW (SEQ ID NO:251); g. an epitope contained within or overlapping with the sequence GQQEQLVFGSGDAVE (SEQ ID NO:252), and / or an epitope contained within or overlapping with the sequence VLVGPQRL (SEQ ID NO:253); and h. an epitope contained within or overlapping with the sequence VLERSPHRPILQAG (SEQ ID NO:254). NO: 254), and / or an epitope contained within or overlapping with the sequence HCKVYSDAQP (SEQ ID NO: 255), and / or an epitope contained within or overlapping with the sequence YVTVLKSWISESVEADVRLR (SEQ ID NO: 256), and / or an epitope contained within or overlapping with the sequence LCRATNFIGVAEKAF (SEQ ID NO: 257). In one embodiment of the present invention, the antibody or antigen-binding fragment thereof binds to one or more FGFR3 epitopes selected from the group consisting of: a. an epitope consisting of the sequence SCPPPGGGPMGPTVWVKDGTGLVPSER (SEQ ID NO: 245),and / or an epitope consisting of the sequence YSCRQRLTQRVL (SEQ ID NO: 246); b. an epitope consisting of the sequence LLAVPAAN (SEQ ID NO: 247), and / or an epitope consisting of the sequence VLERSPHRPILQAG (SEQ ID NO: 248), and / or an epitope consisting of the sequence YVTVLKSWISE (SEQ ID NO: 249), and / or an epitope consisting of the sequence ADVRLR (SEQ ID NO: 250), and / or an epitope consisting of the sequence LCRATNFIGVAEKAFW (SEQ ID NO: 251); c. an epitope consisting of the sequence GQQEQLVFGSGDAVE (SEQ ID NO: 252), and / or an epitope consisting of the sequence VLVGPQRL (SEQ ID NO: 253); and d. an epitope consisting of the sequence VLERSPHRPILQAG (SEQ ID NO: 254), and / or an epitope consisting of the sequence HCKVYSDAQP (SEQ ID NO: 255). NO:255), and / or an epitope consisting of the sequence YVTVLKSWISESVEADVRLR (SEQ ID NO:256), and / or an epitope consisting of the sequence LCRATNFIGVAEKAF (SEQ ID NO:257).

[0010] Also provided herein is an isolated antibody or antigen-binding fragment thereof that specifically binds to FGFR3 or an antigenic fragment thereof, wherein the isolated antibody or antigen-binding fragment binds to the same FGFR3 epitope as the antibody or antigen-binding fragment described herein, or competes with the antibody or antigen-binding fragment described herein for binding to FGFR3.

[0011] For example, the present invention provides an antibody or antigen-binding fragment thereof that specifically binds to FGFR3 or an antigenic fragment thereof, wherein the antibody or antigen-binding fragment thereof is characterized by one or more of the following: binding to FGFR3 with an affinity (K of about 16 nM at 25°C); D ) or greater affinity (e.g., about 16 nM, 12 nM, 10 nM, 7 nM, 5 nM, 4 nM, 3 nM, 2 nM, 1 nM, 0.5 nM, 0.22 nM, 0.2 nM, 0.19 nM, 0.14 nM, 0.1 nM) to monomeric human FGFR3b (e.g., tagged with myc-myc-His6 at the C-terminus) (e.g., in a surface plasmon resonance assay); binds (e.g., in a surface plasmon resonance assay) with an affinity of about 20 nM at 25°C. D) or greater affinity (e.g., about 20 nM, 16 nM, 15 nM, 10 nM, 8 nM, 5 nM, 4 nM, 3 nM, 2 nM, 1 nM, 0.9 nM, 0.65 nM, 0.3 nM, 0.28 nM, 0.2 nM, 0.15 nM, 0.1 nM) to monomeric cynomolgus monkey FGFR3b (e.g., tagged with myc-myc-His6 at the C-terminus) (e.g., in a surface plasmon resonance assay); binds (e.g., in a surface plasmon resonance assay) with an affinity of about 70 nM at 25°C; D ) or greater affinity (e.g., about 70 nM, 20 nM, 17 nM, 12 nM, 10 nM, 9 nM, 8 nM, 0.1 nM) to monomeric murine FGFR3b (e.g., tagged with myc-myc-His6 at the C-terminus) (e.g., in a surface plasmon resonance assay); does not significantly bind to monomeric human FGFR3c (e.g., tagged with myc-myc-His6 at the C-terminus) (e.g., in a surface plasmon resonance assay) at 25°C; binds with an affinity of about 0.6 nM or greater (e.g., about 0.58 nM, 0.17 nM, 0.25 nM, 0.30 nM, 0.40 nM, 0.65 nM, 0.70 nM, 0.80 nM, 0.90 nM, 0.90 nM, 0.10 nM, 0.15 nM, 0.16 nM, 0.17 nM, 0.18 nM, 0.19 nM, 0.21 nM, 0.22 nM, 0.23 nM, 0.24 nM, 0.26 nM, 0.27 nM, 0.28 nM, 0.29 nM, 0.30 nM, 0.31 nM, 0.32 nM, 0.33 nM, 0.34 nM, 0.36 nM, 0.37 nM, 0.38 nM, 0.39 nM, 0.40 nM, 0.51 nM, 0.5 1 nM, 0.11 nM, 0.04 nM, 0.03 nM, 0.02 nM, 0.01 nM, 0.023 nM, 0.061 nM, 0.031 nM, 0.016 nM, 0.034 nM, 0.027 nM) binds to dimeric human FGFR3b (e.g., tagged with mouse Fc (mFc) at the C-terminus) (e.g., in a surface plasmon resonance assay); 200 nM antibody blocks the binding of FGF1 acidic to human FGFR3b-mFc by about 68% or more (e.g., 90% or 05%); the antibody binds to monomeric or dimeric human FGFR3b at a K of 0.05 or higher; the antibody binds to monomeric or dimeric human FGFR3b at a K of 0.05 or higher; the antibody binds to monomeric or dimeric human FGFR3b at a K of 0.05 or higher; the antibody binds to monomeric or dimeric human FGFR3b at a K of 0.05 or higher; the antibody binds to monomeric or dimeric human FGFR3b at a K of 0.05 or higher; the antibody binds to monomeric or dimeric human FGFR3b at a K of 0.05 or higher. D K values vary by about 0.1 nM D Binds to monomeric cynomolgus monkey and monomeric mouse FGFR3b; with an IC of approximately 15 nM 50 or lower concentrations (e.g., an IC of about 1 nM, 2 nM, or 3 nM) 50 ) blocks the binding of 4 nM human FGFR3b-mFc to human FGF1 acidic protein; competes with another anti-FGFR3 antibody as listed in Table 3-1 herein for binding to hFGFR3b.mmH; with an IC of about 18 nM 50 or lower concentrations (e.g., about 0.51 nM, 0.5 nM, 0.61 nM, 0.6 nM, or 0.012 nM) to block intracellular signaling in an engineered IL-3-dependent Ba / F3 murine hematopoietic cell line that has been genetically modified to stably express wild-type or S249C mutant human fibroblast growth factor receptor 3b (the murine hematopoietic cell line has been stimulated with, e.g., about 5 micrograms / ml human heparin and, e.g., about 1 nM human FGF1 ligand); at concentrations below the IC for50 Blocking intracellular signaling in an engineered IL-3-dependent Ba / F3 murine hematopoietic cell line that has been genetically modified to stably express S249C mutant human fibroblast growth factor receptor 3b (the murine hematopoietic cell line has been stimulated with, for example, about 5 micrograms / ml of human heparin and, for example, about 1 nM of human FGF1 ligand); blocking intracellular signaling in an engineered IL-3-dependent Ba / F3 murine hematopoietic cell line that has been genetically modified to stably express wild-type human fibroblast growth factor receptor 3b (the murine hematopoietic cell line has been stimulated with, for example, about 1 nM of human FGF1 ligand and, for example, about 5 micrograms / ml of human heparin); blocking dimerization of FGFR3 (e.g., wild-type or S249C mutant) with greater inhibition than that of REGN6331 as measured, for example, in a non-reducing SDS-PAGE assay; reducing the expression of FGFR3 (e.g., wild-type or S249C mutant) in a subject to which the antibody or fragment is administered. the invention also provides the invention claims a method for increasing the size of bladder cancer tumors expressing FGFR3 (e.g., S249C mutant) in a subject to which the antibody or fragment is administered (e.g., a bladder cancer tumor expressing FGFR3 (e.g., S249C mutant)); reducing CD73 expression in a tumor (e.g., a bladder cancer tumor expressing FGFR3 (e.g., S249C mutant)) in a subject to which the antibody or fragment is administered; inhibiting MAPK phosphorylation induced by FGF1 / heparin stimulation in BaF3 cells expressing wild-type FGFR3 (e.g., S249C mutant); inhibiting the proliferation of UMUC14 bladder cancer cells expressing the endogenous FGFR3 S249C mutation (e.g., in a cancer cell spheroid proliferation assay); inhibiting tumor growth of the bladder cancer cell line UMUC14 expressing FGFR3 (e.g., S249C mutation) in a mouse (e.g., SCID mouse) xenograft model; inhibiting CD73-dependent adenosine-mediated suppression of immune cell activation; increasing CD8 / CD4 and / or CD8+ / T in tumor tissues having tumor cells expressing FGFR3 (e.g., S249C mutant); reg the ratio of α to β-actin; inhibiting FGF3-mediated activation of CD73 expression and / or enzymatic activity (e.g., adenosine production) (e.g., on tumor cells expressing FGFR3 (e.g., S249C mutant)); inhibiting FGFR3-dependent adenosine-mediated suppression of immune cells; inhibiting the growth of BaF3 cells expressing the FGFR3 double mutants S249C and V557M or S249C and V557L, wherein the antibody or antigen-binding fragment comprises an immunoglobulin chain comprising any of the amino acid sequences as listed herein.

[0012] The present invention also provides a complex comprising such an antibody or an antigen-binding fragment thereof that binds to FGFR3 or an antigenic fragment thereof, which is also part of the present invention.

[0013] Also within the scope of the invention are pharmaceutical formulations comprising an anti-FGFR3 antibody or fragment as set forth herein and a pharmaceutically acceptable carrier.

[0014] The present invention further provides: an isolated polypeptide comprising an amino acid sequence selected from the group consisting of: SEQ ID NO: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80 ,82,84,86,88,90,92,94,96,98,100,102,104,106,108,110,112,114 ,116,118,120,122,124,126,128,130,132,134,136,138,140,142,14 4, 146, 148, 150, 153, 155, 157, 159, 161, 163, 165, 167, 169, 171, 173, 175, 177, 179, 181, 183, 185, 187, 189, 191, 193, 195, 197, 199, 201, 203, 205, 207, 209, 211, 213, 215, 217, 219, 221, 223, 225, 227, 229 and 231; and an isolated polynucleotide encoding any one or more of said polypeptides, for example comprising a nucleotide sequence selected from the group consisting of: SEQ ID NO:1,3,5,7,9,11,13,15,17,19,21,23,25,27,29,31,33,35,37,39,41,43,45,47,49,51,53,55,57,59,61,63,65,67,69, 71, 73, 75, 77, 79, 81, 83, 85, 87, 89, 91, 93, 95, 97, 99, 101, 103, 105, 107, 109, 111, 113, 115, 117, 119, 121, 123, 125, 127, 12 9, 131, 133, 135, 137, 139, 141, 143, 145, 147, 149, 151, 152, 154, 156, 158, 160, 162, 164, 166, 168, 170, 172, 174, 176, 178, 180, 182, 184, 186, 188, 190, 192, 194, 196, 198, 200, 202, 204, 206, 208, 210, 212, 214, 216, 218, 220, 222, 224, 226, 228, and 230. The present invention also includes mediators comprising a polynucleotide as listed herein.The invention also provides host cells (eg, eukaryotic or mammalian cells, such as CHO cells) comprising a polynucleotide as listed herein.

[0015] The present invention also provides a method for preparing an anti-FGFR3 antibody or fragment as set forth herein, comprising the steps of introducing a polynucleotide encoding a chain of the antibody or fragment into a host cell (e.g., a CHO cell), and incubating the host cell comprising the polynucleotide in a culture medium under conditions favorable for expression of the chain, and optionally isolating the antibody or fragment from the host cell and / or culture medium.

[0016] The present invention further provides a method for administering an anti-FGFR3 antibody or fragment as set forth herein to a subject, the method comprising introducing (e.g., by injection, e.g., intramuscularly, intravenously, or subcutaneously) the antibody or fragment into the subject.

[0017] The present invention also provides a method for treating or preventing an FGFR3-mediated disorder (e.g., cancer (e.g., mediated by cancer cells expressing the FGFR3 S249C mutation), bladder cancer, brain cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, gastric cancer, head and neck cancer, kidney cancer, lung cancer, multiple myeloma, ovarian cancer, pancreatic cancer, urothelial cancer, achondroplasia, Crouzon syndrome with acanthosis nigricans, epidermal nevus, hypochondroma; lacrimo-auriculo-dento-digital (LADD) syndrome, Muenke syndrome, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), and / or thanatophoric dysplasia) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an anti-FGFR3 antibody or fragment.

[0018] The present invention provides a method for reducing metastasis (e.g., CD73-dependent or adenosine-dependent) of tumor cells expressing FGFR3 (e.g., S249C mutant), reducing the concentration of adenosine in tumors expressing FGFR3 (e.g., S249C mutant), reducing CD73-dependent catalysis of AMP to adenosine by tumors expressing FGFR3 (e.g., S249C mutant), and / or inhibiting adenosine-mediated suppression of T cell function in tumors expressing FGFR3 (e.g., S249C mutant) in a subject in need thereof (e.g., a subject having cancer such as bladder cancer), the method comprising administering to the subject a therapeutically effective amount of an anti-FGFR3 antibody or fragment. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1BaF3 / FGFR3 WT (top, left, and right) and BaF3 / FGFR3_S249C (bottom, left, and right) cells were treated with H4H30063P (left, top, and bottom) or H4H30102P2 (right, top, and bottom) along with titrations of a comparator antibody (REGN6331) and isotype-matched negative controls (REGN1945, REGN1932) in the presence of 1 nM FGF1 and 5 μg / ml heparin. Cell growth was determined using CellTiter-Glo, which measures ATP levels.

[0020] Figure 2 Non-reducing and reducing SDS-PAGE analysis of FGFR3 dimerization in the presence of various concentrations of H4H30063P or COMP6331 (REGN6331) demonstrates the mobility of FGFR3 dimers and monomers.

[0021] Figure 3 Western blot analysis of phosphorylated MAPK from BaF3 / hFGFR3b WT (wild type) in vitro in the absence of antibody (-), the presence of 100 nM control antibody (ConIg; REGN6331), or the presence of 100 nM H4H30063P (with or without FGF1 and heparin stimulation).

[0022] Figure 4 .Use a series of concentrations (Log 10 Proliferation of UMUC14 bladder cancer cells treated with a control antibody (IgG control), H4H30063P, H4H30071P, or REGN6331 relative to untreated cells.

[0023] Figure 5 UMUC14 tumor size (mm) over time in xenografted SCID mice treated with control antibody (10 mg / kg), H4H30063P (3 mg / kg or 10 mg / kg), or REGN6331 (3 mg / kg or 10 mg / kg) 3 ).

[0024] Figure 6 Western blot analysis of CD73 protein expression in in vitro UMUC14 cells treated with control antibody (Con) or H4H30063P (FGFR3 Ab) or AZD4547 (FGFR TKI) at concentrations of 1 nM, 10 nM, and 100 nM.

[0025] Figure 7Western blot analysis of CD73 protein expression in in vivo UMUC14 cells from xenografted mice treated with control antibody (Con) or H4H30063P (FGFR3 Ab).

[0026] Figure 8 .From Figure 7 Quantification of western blot band intensity of CD73 / actin in the blot.

[0027] Figure 9 . Western blot analysis of CD73 protein expression in cell lines expressing empty mediator (EV), wild-type FGFR3 (FGFR3), FGFR3-TACC3 mutant, FGFR3 S249C mutant, or FGFR3 Y375C mutant.

[0028] Figure 10 (A to C). Western blot analysis of CD73 protein expression in tumor cells from xenografted SCID mice expressing (A) empty mediator (EV) or (B) FGFR3 S249C mutant or (C) FGFR3-TACC3 mutant.

[0029] Figure 11 (A to B). Western blot analysis of the expression of CD73 protein levels in Fadu S249C tumor cells in xenograft mice treated with control antibody, H4H30063P antibody, or AZD4547 (B) and graphical quantification of band intensity (B).

[0030] FIG12 (A to B). FGFR3 antibodies inhibit the proliferation of BaF3 cells expressing the TKI resistance mutation V557L / M.

[0031] Figure 13 .HDX epitope mapping results for anti-FGFR3b H4H30117P2 and H4H30063P.

[0032] Figure 14 .HDX epitope mapping results for anti-FGFR3b H4H30045P and H4H30108P2.

[0033] Figure 15 HDX protection provided by FGFR3 antibodies. Regions with higher than 20% and 25% HDX protection are shown.

[0034] Figure 16 (A to B). HDX epitope mapping results of FGFR3 antibodies.

[0035] Figure 17. Results of HDX epitope mapping for H4H30063P. The accompanying figure discloses SEQ ID NO: 238.

[0036] Figure 18 . Results of HDX epitope mapping for H4H30108P2. The accompanying figure discloses SEQ ID NO: 238.

[0037] Figure 19 Results of HDX epitope mapping for H4H30117P2. The accompanying figure discloses SEQ ID NO: 238.

[0038] Figure 20 . Results of HDX epitope mapping for H4H30045P. The accompanying figure discloses SEQ ID NO: 238.

[0039] Figure 21 .Exemplary hydrogen-deuterium exchange mass spectrometry experimental process. DETAILED DESCRIPTION

[0040] The present invention provides anti-FGFR3 antibodies that exhibit excellent in vitro and in vivo properties. In certain embodiments, the antibodies of the present invention exhibit stronger binding to human monomeric FGFR3b, while not exhibiting such binding to FGFR3c. This characteristic contributes to a method for treating cancer with greater targeting, i.e., being able to inhibit the b isoform but not the c isoform. In contrast, it was observed that Bioclin Therapeutics' anti-FGFR3 antibody B-701 exhibits binding to FGFR3c. Relative to B-701, the anti-FGFR3 antibodies herein also exhibit excellent biological activity, including, for example, greater inhibition of FGFR3b dimerization, in vitro cancer cell proliferation, and tumor growth in a mouse xenograft model.

[0041] FGFR3

[0042] The term "FGFR3" refers to monomeric or dimeric human FGFR3b to which the antibodies and antigen-binding fragments thereof of the present invention specifically bind.

[0043] Fibroblast growth factor receptor 3 (FGFR3) belongs to a family of structurally related tyrosine kinase receptors that includes four distinct genes (FGFR1 to 4). These receptors possess three glycosylated extracellular immunoglobulin-like domains (Ig-like domains), a transmembrane domain, and a split intracellular tyrosine kinase domain. Ligand binding induces FGFR dimerization, leading to autophosphorylation of the kinase domain and interaction with and phosphorylation of effector signaling proteins. Alternative mRNA splicing mechanisms generate numerous different receptor isoforms with varying ligand specificities. The isoforms FGFR3b and FGFR3c arise from mutually exclusive splicing events, in which the second half of the third Ig-like domain is encoded by either 151 nucleotides in exon 8 or 145 nucleotides in exon 9. These two isoforms have distinct tissue distributions: for example, FGFR3b is the predominant form in epithelial cells, while FGFR3c is the predominant form in chondrocytes.

[0044] Mutations in FGFR3 are associated with autosomal dominant dwarfism and craniosynostosis syndromes, such as hypochondroma, achondroplasia, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), thanatophoric dysplasia, Crouzon syndrome with acanthosis nigricans, and Muenke coronal craniosynostosis. Reports have demonstrated that these mutations cause constitutive activation of the receptor.

[0045] In addition, FGFR3 has a carcinogenic effect in human cancers. In fact, somatic activating mutations in FGFR3 have been reported in multiple myeloma and recently in two epithelial malignancies (i.e., bladder cancer and cervical cancer). FGFR3 is a driving factor in muscle-invasive bladder cancer (MIBC). See Cappellen et al., Frequent activatingmutations of FGFR3 in human bladder and cervix carcinomas Nat Genet 1999 23:18–20; Chesi et al., Frequent translocation t(4;14)(p16.3;q32.3) in multiplemyeloma is associated with increased expression and activating mutations offibroblast growth factor receptor 3Nat Genet1997 16:260–264; and Richelda et al. Anovel translocation t(4;14)(p16.3;q32.3) in multiple myeloma involving the fibroblast growth-factor receptor 3gene Blood 1997 90:4062–4070. FGFR3 mutations are rare in multiple myeloma and cervical cancer, but their high frequency in bladder cancer (74% of non-invasive papillary tumors) suggests that constitutive activation of FGFR3 is an important event for bladder tumorigenesis.See Fracchiolla et al., FGFR3 gene mutations associated with human skeletal disorders occur rarely in multiple myeloma Blood 1998 92:2987–2989; Wu et al., Somatic mutations of fibroblast growth factor receptor 3 (FGFR3) are uncommon in carcinomas of theuterine cervix Oncogene 2000 19:5543–5546; Billerey et al. Frequent FGFR3mutations in papillary non-invasive bladder(pTa)tumors Am J Pathol 2001 158:1955–1959; and Van Rhijn et al., The fibroblast growth factor receptor 3(FGFR3)mutation is a strong indicator of superficial bladder cancer with low recurrence rate Cancer Res 2001 61:1265–1268. Many of the mutations identified in bladder tumors are the same activating mutations that cause lethal dysplasia, a fatal form of dwarfism.See Cappellen et al., Frequentactivating mutations of FGFR3 in human bladder and cervix carcinomas NatGenet 1999 23:18–20; Billerey et al., Frequent FGFR3 mutations in papillary non-invasive bladder(pTa)tumors Am J Pathol 2001 158:1955–1959; Van Rhijn et al., The fibroblast growth factor receptor 3(FGFR3)mutation is a strong indicator of superficial bladder cancer with low recurrence rate Cancer Res 2001 61:1265–1268; and Sibley et al., Loss of heterozygosity at4p16.3 and mutation of FGFR3 intransitional cell carcinoma Oncogene 2001 20:686–691. Two of the 117 FGFR3 mutations identified by these groups (A393E and K652Q) do not correspond to lethal developmental dysplasia mutations. The A393E mutation is the same mutation associated with a craniosynostosis syndrome (Crouzon syndrome with acanthosis nigricans), and the K652Q mutation is the same mutation associated with hypochondrogenesis.

[0046] In one embodiment of the invention, the human FGFR3c isoform comprises the following amino acid sequence: ESLGTEQRVVGRAAEVPGPEPGQQEQLVFGSGDAVELSCPPPGGGPMGPTVWVKDGTGLVPSERVLVGPQRLQVLNASHEDSGAYSCRQRLTQRVLCHFSVRVTDAPSSGDDEDGEDEAEDTGVDTGAPYWTRPERMDKKLLAVPAANTVRFRCPAAGNPTPSISWLKNGREFRGEHRIGGIKLRHQQWSLVMESVVPSDRGNYTCVVENKFGSIRQTYTLDVLER SPHRPILQAGLPANQTAVLGSDVEFHCKVYSDAQPHIQWLKHVEVNGSKVGPDGTPYVTVLKTAGANTTDKELEVLSLHNVTFEDAGEYTCLAGNSIGFSHHSAWLVVLPAEEELVEADEAGSVYAG(SEQ ID NO:232)

[0047] In one embodiment of the present invention, the human FGFR3b isoform comprises the following amino acid sequence: ESLGTEQRVVGRAAEVPGPEPGQQEQLVFGSGDAVELSCPPPGGGPMGPTVWVKDGTGLVPSERVLVGPQRLQVLNASHEDSGAYSCRQRLTQRVLCHFSVRVTDAPSSGDDEDGEDEAEDTGVDTGAPYWTRPERMDKKLLAVPAANTVRFRCPAAGNPTPSISWLKNGREFRGEHRIGGIKLRHQQWSLVMESVVPSDRGNYTCVVENKFGSIRQTYTLDVLER S PHRPILQAGLPANQTAVLGSDVEFHCKVYSDAQPHIQWLKHVEVNGSKVGPDGTPYVTVLKSWISESVEADVRLRLANVSERDGGEYLCRATNFIGVAEKAFWLSVHGPRAAEEELVEADEAGSVYAG(SEQ ID NO:233)

[0048] In one embodiment of the present invention, the FGFR3 mentioned herein comprises one or more of the following mutations: S249C, R248C, G372C, Y375C, K650E, or FGFR3-TACC3. See Singh et al. Transforming fusions of FGFR and TACC genes in human glioblastoma. Science (New York, NY) 2012; 337: 1231–1235. Tomlinson et al., Knockdown by shRNA identifies S249C mutant FGFR3 as a potential therapeutic target in bladder cancer, Oncogene 2007 Aug 30 26(40):5889-99; Otsuka et al., Constitutively Active FGFR3 with Lys650GluMutation Enhances Bortezomib Sensitivity in Plasma Cell Malignancy, AnticancerResearch January 2011, 31(1)113-122.

[0049] Antigen binding proteins

[0050] The present invention provides antigen-binding proteins (such as antibodies (e.g., human antibodies, monoclonal antibodies, and recombinant antibodies)) and antigen-binding fragments thereof that specifically bind to FGFR3 proteins (e.g., monomeric or dimeric FGFR3b) or antigenic fragments thereof (e.g., the extracellular domain of FGFR3). In one embodiment of the invention, FGFR3 is an activating mutant (e.g., as discussed herein). Antigen binding proteins that bind to the same epitope on FGFR3 as any of the antigen binding proteins listed herein (e.g., H4H30063P; H4H30089P2; H4H30071P; H4H30066P; H4H30102P2; H4H30076P; H4H30105P2; H4H30108P2; H4H30117P2; H4H30045P; H4H30061P; H4H30095P2; or H4H30093P2), or that compete with such an antigen binding protein for binding to FGFR3, are also part of the invention.

[0051] As used herein, the term "antibody" refers to an immunoglobulin molecule (e.g., IgG) comprising four polypeptide chains (two heavy chains (HC) and two light chains (LC)) interconnected by disulfide bonds. In one embodiment of the invention, each antibody heavy chain (HC) comprises a heavy chain variable region ("HCVR" or "V H ”) (e.g., SEQ ID NO: 2 or a variant thereof) and a heavy chain constant region; and each antibody light chain (LC) comprises a light chain variable region (“LCVR” or “V L ”) (e.g., SEQ ID NO: 10 or a variant thereof) and a light chain constant region (CL). V H and V L The regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDRs), interspersed with regions that are more conserved, termed framework regions (FRs).

[0052] In one embodiment of the invention, the anti-FGFR3 antigen binding protein (e.g., antibody or antigen binding fragment) comprises a heavy chain constant domain of, for example, type IgA (e.g., IgA1 or IgA2), IgD, IgE, IgG (e.g., IgG1, IgG2, IgG3, and IgG4 (e.g., comprising S228P and / or S108P mutations)), or IgM. In one embodiment of the invention, the antigen binding protein (e.g., antibody or antigen binding fragment) comprises a light chain constant domain of, for example, type κ or type λ. In one embodiment of the invention, the V constant domains as listed herein are H linked to a human heavy chain constant domain (e.g., IgG), and as listed herein L Linked to a human light chain constant domain (e.g., kappa). The invention includes antigen binding proteins comprising the variable domains listed herein linked to heavy and / or light chain constant domains (e.g., as listed herein) (e.g., H4H30063P; H4H30089P2; H4H30071P; H4H30066P; H4H30102P2; H4H30076P; H4H30105P2; H4H30108P2; H4H30117P2; H4H30045P; H4H30061P; H4H30095P2; or H4H30093P2).

[0053] In one embodiment of the invention, the amino acid assignments to each framework or CDR domain are according to the definitions in Sequences of Proteins of Immunological Interest, Kabat et al.; National Institutes of Health, Bethesda, Md.; 5th Edition; NIH Publ. No. 91-3242 (1991); Kabat (1978) Adv. Prot. Chem. 32: 1-75; Kabat et al., (1977) J. Biol. Chem. 252: 6609-6616; Chothia et al., (1987) J Mol. Biol. 196: 901-917 or Chothia et al., (1989) Nature 342: 878-883. Thus, the present invention includes proteins comprising V H CDR and V L CDRs of antibodies and antigen-binding fragments, wherein V H and V L comprising an amino acid sequence as set forth herein (or a variant thereof), wherein the CDRs are defined, for example, according to Kabat and / or Chothia.

[0054] FGFR3 binding proteins as described herein can be the antigen binding fragment of an antibody. As used herein, the term "antigen binding portion" or "antigen binding fragment" of an antibody refers to an immunoglobulin molecule (preferably, a complete antibody is IgG) that binds to an antigen but does not contain all sequences in the sequence of a complete antibody. Non-limiting examples of antigen binding fragments include: (i) Fab fragments; (ii) F(ab')2 fragments; (iii) Fd fragments; (iv) Fv fragments; (v) single-chain Fv (scFv) molecules; and (vi) dAb fragments; It is composed of amino acid residues that mimic the hypervariable region of an antibody (e.g., separated complementarity determining regions (CDRs), such as CDR3 peptides), or limited FR3-CDR3-FR4 peptides. As used herein, other engineered molecules (such as domain-specific antibodies, single domain antibodies, one-arm antibodies, domain-deleted antibodies, chimeric antibodies, CDR-grafted antibodies, double-chain antibodies, three-chain antibodies, four-chain antibodies, microantibodies, and small modular immune drugs (SMIPs)) are also encompassed within the description "antigen binding fragment".

[0055] "Isolated" antigen-binding proteins (e.g., antibodies or antigen-binding fragments thereof), polypeptides, polynucleotides, and mediators are at least partially free of other biological molecules from the cells or cell cultures from which they are produced. Such biological molecules include nucleic acids, proteins, other antibodies or antigen-binding fragments, lipids, carbohydrates, or other substances, such as cell debris and growth medium. The isolated antigen-binding proteins may further be at least partially free of expression system components, such as biological molecules from the host cells or their growth medium. Generally speaking, the term "isolated" is not intended to refer to the complete absence of such biological molecules (e.g., trace or insignificant amounts of impurities may remain), nor to the absence of water, buffers, or salts, or components of a pharmaceutical formulation comprising the antigen-binding protein (e.g., antibody or antigen-binding fragment).

[0056] The amino acid sequences of the polypeptides of the present invention and the nucleotide sequences of the polynucleotides of the present invention are listed in Table A and Table B below, respectively.

[0057] Table A. Amino acid sequences of exemplary immunoglobulin chains of the invention

[0058]

[0059]

[0060] *In one embodiment of the invention, the heavy chain lacks the C-terminal lysine.

[0061] Table B. Nucleotide sequences of exemplary polynucleotides encoding immunoglobulin chains of the invention

[0062]

[0063] *In one embodiment of the invention, the heavy chain lacks the codon encoding the C-terminal lysine.

[0064] The sequences of the immunoglobulin chains of the anti-FGFR3 antibodies and antigen-binding fragments of the invention are listed below. Thus, the invention includes any antibody or antigen-binding fragment thereof comprising a HCVR and LCVR having the amino acid sequences listed below, or a HCVR and LCVR having their HCDRs and LCDRs, respectively.

[0065] H4H30063P

[0066] HCVR nucleotide sequenceCAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGTCCCTCACCTGCACTGTCTCTGGTGACTCCATTAATAGTTACTTCTGGAGCTGGATCCGGCAGTTGCCAGGGAAGGAACTGGAGTGGATTGGCCATATCTATTCTAGTGGGAGTAC CAGATACAACCCCTCCCTCCAGAGTCGAGTCACCATATCAATAGACACGTCCAAGAACCAGTTCTCCCTGAAGCTGAGTTCTGTGACCGCTGCGGACACGGCCGTATATTACTGTGCGAGGGGCGCCAGCGCAGTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA(SEQ ID NO:1)

[0067] HCVR amino acid sequence

[0068] QVQLQESGPGLVKPSETLSLTCTVS GDSINSYF WSWIRQLPGKELEWIGH IYSSGST RYNPSLQSRVTISIDTSKNQFSLKLSSVTAADTAVYYC ARGASAVDY WGQGTLVTVSS (SEQ ID NO: 2)

[0069] HCDR1 nucleotide sequence

[0070] GGT GAC TCC ATT AAT AGT TAC TTC

[0071] (SEQ ID NO: 3)

[0072] HCDR1 amino acid sequence

[0073] GDSINSYF

[0074] (SEQ ID NO:4)

[0075] HCDR2 nucleotide sequence

[0076] ATC TAT TCT AGT GGG AGT ACC

[0077] (SEQ ID NO:5)

[0078] HCDR2 amino acid sequence

[0079] IYSSGST

[0080] (SEQ ID NO:6)

[0081] HCDR3 nucleotide sequence

[0082] GCG AGG GGC GCC AGC GCA GTT GAC TAC

[0083] (SEQ ID NO:7)

[0084] HCDR3 amino acid sequence

[0085] ARGASAVDY

[0086] (SEQ ID NO:8)

[0087] LCVR nucleotide sequence

[0088] GAAATTGTGTTGACGCAGTCCAGGCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGACCAGTCAGAGTATTAGCAGCGGCTATTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATCCAGA AGGGCCACTGGCATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTGGAGCCTGAAGACTTTGTAGTGTATTACTGTCAACAATATGGTAGCTCACCATACACTTTTGGCCAGGGGACCAAGCTGGAGATCAAA

[0089] (SEQ ID NO:9)

[0090] LCVR amino acid sequence

[0091] EIVLTQSPGTLSLSPGERATLSCRTS QSISSGY LAWYQQKPGQAPRLLIY GAS RRATGIPDRFSGSGSGTDFTLTISRLEPEDFVVYYC QQYGSSPYT FGQGTKLEIK

[0092] (SEQ ID NO: 10)

[0093] LCDR1 nucleotide sequence

[0094] CAG AGT ATT AGC AGC GGC TAT

[0095] (SEQ ID NO: 11)

[0096] LCDR1 amino acid sequence QSISSGY

[0097] (SEQ ID NO: 12)

[0098] LCDR2 nucleotide sequence

[0099] GGT GCA TCC

[0100] (SEQ ID NO: 13)

[0101] LCDR2 amino acid sequence

[0102] GAS

[0103] (SEQ ID NO: 14)

[0104] LCDR3 nucleotide sequence

[0105] CAA CAA TAT GGT AGC TCA CCA TAC ACT

[0106] (SEQ ID NO: 15)

[0107] LCDR3 amino acid sequence

[0108] QQYGSSPYT

[0109] (SEQ ID NO: 16)

[0110] Heavy chain nucleotide sequence

[0111]

[0112] (SEQ ID NO:17)

[0113] Heavy chain amino acid sequence QVQLQESGPGLVKPSETLSLTCTVSGDSINSYFWSWIRQLPGKELEWIGHIYSS GSTRYNPSLQSRVTISIDTSKNQFSLKLSSVTAADTAVYYCARGASAVDYWGQGTLVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

[0114] (SEQ ID NO:18)

[0115] Light chain nucleotide sequence: GAAATTGTGTTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGACCAGTCAGAGTATTAGCAGCGGCTATTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATCCAGAAGGGCCACTGGCATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTGGAGCCTGAAGACTTTGTAGTGTATTACTGTCAACAATATGGTAGCTCACCATACACTTTTGGCCAGGGGACCAAGCTGGAGATCAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG

[0116] (SEQ ID NO:19)

[0117] Light chain amino acid sequence

[0118] EIVLTQSPGTLSLSPGERATLSCRTSQSISSGYLAWYQQKPGQAPRLLIYGASRRATGIPDRFSGSGSG TDFTLTISRLEPEDFVVYYCQQYGSSPYTFGQGTKLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0119] (SEQ ID NO:20)

[0120] H4H30066P

[0121] HCVR nucleotide sequence

[0122] CAGGTGCAGCTGGTACAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGTTTCCGGATACACCCTCACTGAATTATCCATGCACTGGGTGCGACAAGCTCCTGGAAAAGGGCTTGAGTGGATGGGAGGTTTTGATCCTGAAGATGGTGAAATAATCTACGCACAGAAGTTCCAGGGCAGAGTCACCATGACCGAGGACACATCTACAGACACAGCCTACATGGACCTGAGCAGTCTGACATCTGAAGACACGGCCGTGTATTACTGTGCAACGGAGAAGCAGCAACTGGTACGAAAATACTACTTCTACTACGGTTTGGCCGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCA

[0123] (SEQ ID NO:21)

[0124] HCVR amino acid sequence

[0125] QVQLVQSGAEVKKPGASVKVSCKVS GYTLTELS MHWVRQAPGKGLEWMGG FDPEDGEI IYAQKFQGRVTMTEDTSTDTAYMDLSSLTSEDTAVYYC ATEKQQLVRKYYFYYGLAV WGQGTTVTVSS

[0126] (SEQ ID NO:22)

[0127] HCDR1 nucleotide sequence

[0128] GGA TAC ACC CTC ACT GAA TTA TCC

[0129] (SEQ ID NO:23)

[0130] HCDR1 amino acid sequence G Y T L T E L S

[0131] (SEQ ID NO:24)

[0132] HCDR2 nucleotide sequence

[0133] TTT GAT CCT GAA GAT GGT GAA ATA

[0134] (SEQ ID NO:25)

[0135] HCDR2 amino acid sequence

[0136] FDPEDGEI

[0137] (SEQ ID NO:26)

[0138] HCDR3 nucleotide sequence

[0139] GCA ACG GAG AAG CAG CAA CTG GTA CGA AAA TAC TAC TTC TAC TAC GGT TTGGCC GTC

[0140] (SEQ ID NO: 27)

[0141] HCDR3 amino acid sequence

[0142] ATEKQQLVRKYYFYYGLAV(SEQ ID NO:28)

[0143] LCVR nucleotide sequence

[0144] GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGTTATTTAAATTGGTATCAGCAGAAACCAGGGAAAGTCCCTAAGCTCCTGATCTATGCTGCATCCAGTT TGCAAAGTGGGGTCCCATCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTCCCCCATTCACTTTCGGCCCTGGGACCAAAGTGGATATCAAA

[0145] (SEQ ID NO: 29)

[0146] LCVR amino acid sequence

[0147] DIQMTQSPSSLSASVGDRVTITCRAS QSISSY LNWYQQKPGKVPKLLIY AASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYC QQSYSPPFT FGPGTKVDIK

[0148] (SEQ ID NO:30)

[0149] LCDR1 nucleotide sequence

[0150] CAG AGC ATT AGC AGT TAT

[0151] (SEQ ID NO:31)

[0152] LCDR1 amino acid sequence

[0153] QSISSY

[0154] (SEQ ID NO:32)

[0155] LCDR2 nucleotide sequence

[0156] GCT GCA TCC

[0157] (SEQ ID NO:33)

[0158] LCDR2 amino acid sequence

[0159] AAS

[0160] (SEQ ID NO:34)

[0161] LCDR3 nucleotide sequence

[0162] CAA CAG AGT TAC AGT CCC CCA TTC ACT

[0163] (SEQ ID NO:35)

[0164] LCDR3 amino acid sequence

[0165] QQSYSPPFT

[0166] (SEQ ID NO:36)

[0167] Heavy chain nucleotide sequence

[0168]

[0169] (SEQ ID NO:37)

[0170] Heavy chain amino acids QVQLVQSGAEVKKPGASVKVSCKVSGYTLTELSMHWVRQAPGKGLEWMGGFDPEDGEI IYAQKFQGRVTMTEDTSTDTAYMDLSSLTSEDTAVYYCATEKQQLVRKYYFYYGLAVWGQGTTVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

[0171] (SEQ ID NO:38)

[0172] Light chain nucleotide sequence: GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGTTATTTAAATTGGTATCAGCAGAAACCAGGGAAAGTCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTCCCCCATTCACTTTCGGCCCTGGGACCAAAGTGGATATCAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG

[0173] (SEQ ID NO:39)

[0174] Light chain amino acids DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKVPKLLIYAASSLQSGV PSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSPPFTFGPGTKVDIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0175] (SEQ ID NO:40)

[0176] H4H30071P

[0177] HCVR nucleotide sequence

[0178] CAGGTACAGCTGCAGCAGTCAGGTCCAGGACTGGTGAAGCCCTCGCAGACCCTCTCACTCACCTGTGCCATCTCCGGGGACAGTGTCTCTAGGAACAGTGCTGCTTGGAACTGGATCAGGCAGTCCCCATCGAGTGGCCTTGAGTGGCTGGGAAGGACATACTACAGGTCCAAGTGGTTTTATGATTATGCAATATCTGTGAAAAGTCGAATAACCGTCAACCCAGACACATCCAAGAACCAATTCTCCCTTCACCTGAACTCTGTGACTCCCGAAGACACGGCTGTCTATTACTGTGCGAGAGGCTACGGTGGCTACGAGGACTACTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA

[0179] (SEQ ID NO:41)

[0180] HCVR amino acid sequence

[0181] QVQLQQSGPGLVKPSQTLSLTCAIS GDSVSRNSAA WNWIRQSPSSGLEWLGR TYYRSKWFY DYAISVKSRITVNPDTSKNQFSLHLNSVTPEDTAVYYC ARGYGGYEDYFDY WGQGTLVTVSS

[0182] (SEQ ID NO:42)

[0183] HCDR1 nucleotide sequence

[0184] GGG GAC AGT GTC TCT AGG AAC AGT GCT GCT

[0185] (SEQ ID NO:43)

[0186] HCDR1 amino acid sequence

[0187] G D S V S R N S A A

[0188] (SEQ ID NO:44)

[0189] HCDR2 nucleotide sequence

[0190] ACA TAC TAC AGG TCC AAG TGG TTT TAT

[0191] (SEQ ID NO:45)

[0192] HCDR2 amino acid sequence

[0193] TYYRSKWFY

[0194] (SEQ ID NO:46)

[0195] HCDR3 nucleotide sequence

[0196] GCG AGA GGC TAC GGT GGC TAC GAG GAC TAC TTT GAC TAC

[0197] (SEQ ID NO:47)

[0198] HCDR3 amino acid sequence

[0199] ARGYGGYEDYFDY

[0200] (SEQ ID NO:48)

[0201] LCVR nucleotide sequence

[0202] GACATCCAGATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGTCGGGCGAGTCAGGGTATTAGCAGCTGGTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGGTGCATCCAGTT TGCAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTACTTTTGTCAACAGGGTAGCAGTTTCCCGTACACTTTTGGCCAGGGGACCAAGCTGGAGATCAAA

[0203] (SEQ ID NO:49)

[0204] LCVR amino acid sequence

[0205] DIQMTQSPSSVSASVGDRVTITCRAS QGISSW LAWYQQKPGKAPKLLIY GASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYFC QQGSSFPYT FGQGTKLEIK

[0206] (SEQ ID NO:50)

[0207] LCDR1 nucleotide sequence

[0208] CAG GGT ATT AGC AGC TGG

[0209] (SEQ ID NO:51)

[0210] LCDR1 amino acid sequence

[0211] QGISSW

[0212] (SEQ ID NO:52)

[0213] LCDR2 nucleotide sequence

[0214] GGT GCA TCC

[0215] (SEQ ID NO:53)

[0216] LCDR2 amino acid sequence

[0217] GAS

[0218] (SEQ ID NO:54)

[0219] LCDR3 nucleotide sequence

[0220] CAA CAG GGT AGC AGT TTC CCG TAC ACT

[0221] (SEQ ID NO:55)

[0222] LCDR3 amino acid sequence

[0223] QQGSSFPYT

[0224] (SEQ ID NO:56)

[0225] Heavy chain nucleotide sequence

[0226]

[0227] Heavy chain amino acids

[0228] QVQLQQSGPGLVKPSQTLSLTCAISGDSVSRNSAAWNWIRQSPSSGLEWLGRTYYRSKWFYDYAISVKS RITVNPDTSKNQFSLHLNSVTPEDTAVYYCARGYGGYEDYFDYWGQGTLVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

[0229] (SEQ ID NO:58)

[0230] Light chain nucleotide sequence

[0231] GACATCCAGATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGTCGGGCGAGTCAGGGTATTAGCAGCTGGTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGGTGCATCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTACTTTTGTCAACAGGGTAGCAGTTTCCCGTACACTTTTGGCCAGGGGACCAAGCTGGAGATCAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG

[0232] (SEQ ID NO:59)

[0233] Light chain amino acids

[0234] DIQMTQSPSSVSASVGDRVTITCRASQGISSWLAWYQQKPGKAPKLLIYGASSLQSGVPSRFSGSGSGT DFTLTISSLQPEDFATYFCQQGSSFPYTFGQGTKLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0235] (SEQ ID NO:60)

[0236] H4H30089P2

[0237] HCVR nucleotide sequence

[0238] GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGAGGGTCCCTGAGACTCTCCCTGTATAGTCTCTGGATTCATCTTCAGTAGTTATGAAATGAGCTGGCTCCGCCAGGCTCCAGGGAAGGGCCTGGAGTGGATTTCATATTAGTAGTAGTGTGTCGTGTCTACTCTCT ATGCAGACTCTGTGAAGGGCCGATTCACCATCTCCAGAGAGAGCGCCAAGAATTCACTGTATCTGGAAATGAATAGTCTGAGAGCCGAAGACACGGCTATATATTTGTACGAAAGTGGGATAGTGGCCCATTTGACTCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCCA

[0239] (SEQ ID NO:61)

[0240] HCVR

[0241] EVQLVESGGGLVQPGGSLRLSCIVS GFIFSSYE MSWLRQAPGKGLEWISY ISSSGRVI YYADSWKGRFTISRDSAKNSLYLEMNSLRAEDTAIYYC TRKWDSSGPFDF WGQGTLVTVSS(SEQ ID NO:62)

[0242] HCDR1

[0243] GGA TTC ATC TTC AGT AGT TAT GAA

[0244] (SEQ ID NO:63)

[0245] HCDR1

[0246] GFIFSSYE

[0247] (SEQ ID NO:64)

[0248] HCDR2

[0249] ATT AGT AGT AGT GGT CGT GTC ATA

[0250] (SEQ ID NO:65)

[0251] HCDR2 amino acid sequence

[0252] ISSSGRVI

[0253] (SEQ ID NO:66)

[0254] HCDR3 nucleotide sequence

[0255] ACG AGA AAG TGG GAT AGT AGT GGC CCA TTT GAC TTC

[0256] (SEQ ID NO:67)

[0257] HCDR3 amino acid sequence

[0258] TRKWDSSGPFDF

[0259] (SEQ ID NO:68)

[0260] LCVR nucleotide sequence

[0261] GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTG CAAAGTGGGGTCCCGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCTCCGATCACCTTCGGCCAAGGGACACGACTGGAGATTAAA

[0262] (SEQ ID NO:69)

[0263] LCVR amino acid sequence

[0264] DIQMTQSPSSLSASVGDRVTITCRAS QSISSY LNWYQQKPGKAPKLLIY AAS SLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYC QQSYSTPPITFGQGTRLEIK

[0265] (SEQ ID NO:70)

[0266] LCDR1 nucleotide sequence

[0267] CAG AGC ATT AGC AGC TAT

[0268] (SEQ ID NO:71)

[0269] LCDR1 amino acid sequence

[0270] QSISSY

[0271] (SEQ ID NO:72)

[0272] LCDR2 nucleotide sequence

[0273] GCT GCA TCC

[0274] (SEQ ID NO:73)

[0275] LCDR2 amino acid sequence

[0276] AAS

[0277] (SEQ ID NO:74)

[0278] LCDR3 nucleotide sequence

[0279] CAA CAG AGT TAC AGT ACC CCT CCG ATC ACC

[0280] (SEQ ID NO:75)

[0281] LCDR3 amino acid sequence

[0282] QQSYSTPPIT

[0283] (SEQ ID NO:76)

[0284] Heavy chain nucleotide sequence

[0285]

[0286] (SEQ ID NO:77)

[0287] Heavy chain amino acids EVQLVESGGGLVQPGGSLRLSCIVSGFIFSSYEMSWLRQAPGKGLEWISYISSSGRVI YYADSVKGRFTISRDSAKNSLYLEMNSLRAEDTAIYYCTRKWDSSGPFDFWGQGTLVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

[0288] (SEQ ID NO:78)

[0289] Light chain nucleotide sequence: GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCCCGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCACCTTCGGCCAAGGGACACGACTGGAGATTAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG

[0290] (SEQ ID NO:79)

[0291] Light chain amino acids

[0292] DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGT DFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0293] (SEQ ID NO:80)

[0294] H4H30093P2

[0295] HCVR nucleotide sequence

[0296] CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCAAGCCTGGAGGGTCCCTAAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAATGACTACCCAATGAGCTGGATCCGCCAGGCTCCAGGGAAGGGACTGGAGTGGGTTTCATACATTACTAGCAGTAGTGGTAGTACCATATACTACGCAGACTCTGTGAAGGGCCGATTCACCATCTCCAGGGACAACGCCAAGAACTCACTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTGTATTACTGTGCGAGAGAGGTTGTAGTGGCTACGATTGGGGGCTACTACGGTATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCA

[0297] (SEQ ID NO:81)

[0298] HCVR amino acid sequence

[0299] QVQLVESGGGLVKPGGSLRLSCAAS GFTFNDYP MSWIRQAPGKGLEWVSY ITSSSGSTI YYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYC AREVVVATIGGYYGMDV WGQGTTVTVSS

[0300] (SEQ ID NO:82)

[0301] HCDR1 nucleotide sequence

[0302] GGA TTC ACC TTC AAT GAC TAC CCA

[0303] (SEQ ID NO:83)

[0304] HCDR1 amino acid sequence

[0305] G F T F N D Y P

[0306] (SEQ ID NO:84)

[0307] HCDR2 nucleotide sequence

[0308] ATT ACT AGC AGT AGT GGT AGT ACC ATA

[0309] (SEQ ID NO:85)

[0310] HCDR2 amino acid sequence

[0311] ITSSSGSTI

[0312] (SEQ ID NO:86)

[0313] HCDR3 nucleotide sequence

[0314] GCG AGA GAG GTT GTAGTG GCT ACG ATT GGG GGC TAC TAC GGT ATG GAC GTC

[0315] (SEQ ID NO:87)

[0316] HCDR3 amino acid sequence

[0317] AREVVV AT IGGYYGMDV(SEQ ID NO:88)

[0318] LCVR nucleotide sequence

[0319] GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTG CAAAGTGGGGTCCCGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCTCCGATCACCTTCGGCCAAGGGACACGACTGGAGATTAAA

[0320] (SEQ ID NO:89)

[0321] LCVR amino acid sequence

[0322] DIQMTQSPSSLSASVGDRVTITCRAS QSISSY LNWYQQKPGKAPKLLIY AAS SLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYC QQSYSTPPIT FGQGTRLEIK

[0323] (SEQ ID NO:90)

[0324] LCDR1 nucleotide sequence

[0325] CAG AGC ATT AGC AGC TAT

[0326] (SEQ ID NO:91)

[0327] LCDR1 amino acid sequence

[0328] QSISSY

[0329] (SEQ ID NO:92)

[0330] LCDR2 nucleotide sequence GCT GCA TCC

[0331] (SEQ ID NO:93)

[0332] LCDR2 amino acid sequence

[0333] AAS

[0334] (SEQ ID NO:94)

[0335] LCDR3 nucleotide sequence

[0336] CAA CAG AGT TAC AGT ACC CCT CCG ATC ACC

[0337] (SEQ ID NO:95)

[0338] LCDR3 amino acid sequence

[0339] QQSYSTPPIT

[0340] (SEQ ID NO:96)

[0341] Heavy chain nucleotide sequence

[0342]

[0343] (SEQ ID NO:97)

[0344] Heavy chain amino acids

[0345] QVQLVESGGGLVKPGGSLRLSCAASGFTFNDYPMSWIRQAPGKGLEWVSYITSSSGSTIYYADSVKGRF TISRDNAKNSLYLQMNSLRAEDTAVYYCAREVVVATIGGYYGMDVWGQGTTVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

[0346] (SEQ ID NO:98)

[0347] Light chain nucleotide sequence

[0348] GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCCCGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCACCTTCGGCCAAGGGACACGACTGGAGATTAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG

[0349] (SEQ ID NO:99)

[0350] Light chain amino acids

[0351] DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGT DFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0352] (SEQ ID NO:100)

[0353] H4H30102P2

[0354] HCVR nucleotide sequence

[0355] GAGGTGCAGCTGGTGGAGTCTGGGGGAGACTTGGTACAGCCTGGAGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGTTATGAAATGAACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTTTCATACATTAGTAATAGTGGTTCTACCATATACTACGCAGACTCTGTGAAGGGCCGATTCACCATCTCCAGAGACAACGCCGAGACCTCACTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTTTATTACTGTGCGAGAGAGGGATGGGGCGCATATTGTGCTGGTGATTGCTATTCTGGTTTTGATATTTGGGGCCAAGGGACAATGGTCACCGTCTCTTCA

[0356] (SEQ ID NO:101)

[0357] HCVR amino acid sequence

[0358] EVQLVESGGDLVQPGGSLRLSCAAS GFTFSSYE MNWVRQAPGKGLEWVSY ISNSGSTI YYADSVKGRFTISRDNAETSLYLQMNSLRAEDTAVYYC AREGWGAYCAGDCYSGFDI WGQGTMVTVSS

[0359] (SEQ ID NO:102)

[0360] HCDR1 nucleotide sequence

[0361] GGA TTC ACC TTC AGT AGT TAT GAA

[0362] (SEQ ID NO:103)

[0363] HCDR1 amino acid sequence

[0364] G F T F S S Y E

[0365] (SEQ ID NO:104)

[0366] HCDR2 nucleotide sequence

[0367] ATT AGT AAT AGT GGT TCT ACC ATA

[0368] (SEQ ID NO: 105)

[0369] HCDR2 amino acid sequence

[0370] ISNSGSTI

[0371] (SEQ ID NO: 106)

[0372] HCDR3 nucleotide sequence

[0373] GCG AGA GAG GGA TGG GGC GCA TAT TGT GCT GGT GAT TGC TAT TCT GGT TTTGAT ATT

[0374] (SEQ ID NO: 107)

[0375] HCDR3 amino acid sequence

[0376] AREGWGAYC AG DCYSGFDI(SEQ ID NO:108)

[0377] LCVR nucleotide sequence

[0378] GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTG CAAAGTGGGGTCCCGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCTCCGATCACCTTCGGCCAAGGGACACGACTGGAGATTAAA

[0379] (SEQ ID NO: 109)

[0380] LCVR amino acid sequence

[0381] DIQMTQSPSSLSASVGDRVTITCRAS QSISSY LNWYQQKPGKAPKLLIY AAS SLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYC QQSYSTPPIT FGQGTRLEIK

[0382] (SEQ ID NO: 110)

[0383] LCDR1 nucleotide sequence

[0384] CAG AGC ATT AGC AGC TAT

[0385] (SEQ ID NO: 111)

[0386] LCDR1 amino acid sequence

[0387] QSISSY

[0388] (SEQ ID NO: 112)

[0389] LCDR2 nucleotide sequence

[0390] GCT GCA TCC

[0391] (SEQ ID NO: 113)

[0392] LCDR2 amino acid sequence

[0393] AAS

[0394] (SEQ ID NO: 114)

[0395] LCDR3 nucleotide sequence

[0396] CAA CAG AGT TAC AGT ACC CCT CCG ATC ACC

[0397] (SEQ ID NO: 115)

[0398] LCDR3 amino acid sequence

[0399] QQSYSTPPIT

[0400] (SEQ ID NO: 116)

[0401] Heavy chain nucleotide sequence

[0402]

[0403] Heavy chain amino acids

[0404] EVQLVESGGDLVQPGGSLRLSCAASGFTFSSYEMNWVRQAPGKGLEWVSYISNSGSTIYYADSVKGRFT ISRDNAETSLYLQMNSLRAEDTAVYYCAREGWGAYCAGDCYSGFDIWGQGTMVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

[0405] (SEQ ID NO:118)

[0406] Light chain nucleotide sequence

[0407] GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCCCGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCACCTTCGGCCAAGGGACACGACTGGAGATTAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG

[0408] (SEQ ID NO:119)

[0409] Light chain amino acids

[0410] DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGT DFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0411] (SEQ ID NO:120)

[0412] H4H30076P

[0413] HCVR nucleotide sequence

[0414] GAGGTGCAGCTGGTGGAGTCTGGAGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGGTTCACCGTCAGTAGCAACTACATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAATTATTTATAGCGGTGGTCACACATACTACTCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGACACAATTCCAAGAACACTCTGTATCTTCAAATGAACAGCCTGAGAGGTGGGGACACGGCCGTGTATTACTGTGCGAGAGGGTATACCAGTGGCTGGTACGGATTTGACTTCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA

[0415] (SEQ ID NO:121)

[0416] HCVR amino acid sequence

[0417] EVQLVESGGGLVQPGGSLRLSCAAS GFTVSSNY MSWVRQAPGKGLEWVSI IYSGGHT YYSDSVKGRFTISRHNSKNTLYLQMNSLRGGDTAVYYC ARGYTSGWYGFDF WGQGTLVTVSS

[0418] (SEQ ID NO:122)

[0419] HCDR1 nucleotide sequence

[0420] GGG TTC ACC GTC AGT AGC AAC TAC

[0421] (SEQ ID NO:123)

[0422] HCDR1 amino acid sequence

[0423] G F T V S S N Y

[0424] (SEQ ID NO:124)

[0425] HCDR2 nucleotide sequence

[0426] ATT TAT AGC GGT GGT CAC ACA

[0427] (SEQ ID NO: 125)

[0428] HCDR2 amino acid sequence

[0429] IYSGGHT

[0430] (SEQ ID NO: 126)

[0431] HCDR3 nucleotide sequence

[0432] GCG AGA GGG TAT ACC AGT GGC TGG TAC GGA TTT GAC TTC

[0433] (SEQ ID NO: 127)

[0434] HCDR3 amino acid sequence

[0435] ARGYTSGWYGFDF

[0436] (SEQ ID NO: 128)

[0437] LCVR nucleotide sequence

[0438] GACATCCAGATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGTCGGGCGAGTCAGGGTATTAGCACCTGGTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTT TGCAAAGTGGGGTCCCGTCAAGATTCAGCGGCACTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTATTATTGTCAGCAGACTAACAGTTTCCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA

[0439] (SEQ ID NO: 129)

[0440] LCVR amino acid sequence

[0441] DIQMTQSPSSVSASVGDRVTITCRAS QGISTW LAWYQQKPGKAPKLLIY AAS SLQSGVPSRFSGTGSGTDFTLTISSLQPEDFATYYC QQTNSFPWT FGQGTKVEIK

[0442] (SEQ ID NO: 130)

[0443] LCDR1 nucleotide sequence

[0444] CAG GGT ATT AGC ACC TGG

[0445] (SEQ ID NO: 131)

[0446] LCDR1 amino acid sequence

[0447] QGISTW

[0448] (SEQ ID NO: 132)

[0449] LCDR2 nucleotide sequence

[0450] GCT GCA TCC

[0451] (SEQ ID NO:33)

[0452] LCDR2 amino acid sequence

[0453] AAS

[0454] (SEQ ID NO:34)

[0455] LCDR3 nucleotide sequence

[0456] CAG CAG ACT AAC AGT TTC CCG TGG ACG

[0457] (SEQ ID NO: 133)

[0458] LCDR3 amino acid sequence

[0459] QQTNSFPWT

[0460] (SEQ ID NO: 134)

[0461] Heavy chain nucleotide sequence

[0462]

[0463] (SEQ ID NO:135)

[0464] Heavy chain amino acid sequence

[0465] EVQLVESGGGLVQPGGSLRLSCAASGFTVSSNYMSWVRQAPGKGLEWVSIIYSGGHTYYSDSVKGRFT ISRHNSKNTLYLQMNSLRGGDTAVYYCARGYTSGWYGFDFWGQGTLVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK*

[0466] (SEQ ID NO:136)

[0467] Light chain nucleotide sequence

[0468] GACATCCAGATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGTCGGGCGAGTCAGGGTATTAGCACCTGGTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCCCGTCAAGATTCAGCGGCACTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTATTATTGTCAGCAGACTAACAGTTTCCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG

[0469] (SEQ ID NO:137)

[0470] Light chain amino acid sequence

[0471] DIQMTQSPSSVSASVGDRVTITCRASQGISTWLAWYQQKPGKAPKLLIYAASSLQSGVPSRFSGTGSG TDFTLTISSLQPEDFATYYCQQTNSFPWTFGQGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC*

[0472] (SEQ ID NO:138)

[0473] H4H30105P2

[0474] HCVR nucleotide sequence

[0475] GAGGTGCAGCTGGTGCAGTCTGGAGCAGAGGTGAAAAAGCCCGGGGAGTCTCTGAAGATCTCCTGTAAGGGTTCTGGATACAGCTTTACCAGCTACTGGATCGCCTGGGTGCGCCAGATGCCCGGGAAAGGCCTGGAGTGGATGGGGATCATCTATCCTGGTGACTCTGATACCAGATACAGCCCGTCCTTCCAAGGCCAGGTCACCATGTCAGCCGACAAGTCCATCAGGATCGCCTACCTGCAGTGGAGCAGCCTGAAGGCCTCGGACACCGCCATGTATTATTGTGCGAGACTTGATTATAGCGGCAGCTGGTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA

[0476] (SEQ ID NO:139)

[0477] HCVR amino acid sequence

[0478] EVQLVQSGAEVKKPGESLKISCKGS GYSFTSYW IAWVRQMPGKGLEWMGI IYPGDSDT RYSPSFQGQVTMSADKSIRIAYLQWSSLKASDTAMYYC ARLDYSGSWFDY WGQGTLVTVSS(SEQ ID NO:140)

[0479] HCDR1 nucleotide sequence

[0480] GGA TAC AGC TTT ACC AGC TAC TGG

[0481] (SEQ ID NO:141)

[0482] HCDR1 amino acid sequence

[0483] G Y S F T S Y W

[0484] (SEQ ID NO:142)

[0485] HCDR2 nucleotide sequence

[0486] ATC TAT CCT GGT GAC TCT GAT ACC

[0487] (SEQ ID NO: 143)

[0488] HCDR2 amino acid sequence

[0489] IYPGD SD T

[0490] (SEQ ID NO: 144)

[0491] HCDR3 nucleotide sequence

[0492] GCG AGA CTT GAT TAT AGC GGC AGC TGG TTT GAC TAC

[0493] (SEQ ID NO: 145)

[0494] HCDR3 amino acid sequence

[0495] ARLDYSGSWFDY

[0496] (SEQ ID NO: 146)

[0497] LCVR nucleotide sequence

[0498] GAAATAGTTTTGACACAGAGTCCCGGCACACTGTCACTCTCTCCCGGGGAAAGAGCCACCTTGTCATGTAGAGCAAGTCAGTCAGTCTCTAGCTCTTATCTCGCCTGGTACCAGCAGAAGCCGGGACAGGCCCCTAGACTGCTGATCTACGGGGCAAGTTCC AGGGCCACCGGAATCCCCGACCGGTTCAGTGGAAGCGGAAGCGGAACCGATTTTACTTTGACGATTTCTAGACTGGAGCCAGAGGATTTCGCCGTTTACTATTGTCAACAGTACGGAAGCAGCCCGTGGACGTTTGGCCAGGGCACGAAGGTAGAAATCAAG

[0499] (SEQ ID NO: 147)

[0500] LCVR amino acid sequence

[0501] EIVLTQSPGTLSLSPGERATLSCRAS QSVSSSY LAWYQQKPGQAPRLLIY GAS SRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYC QQYGSSPWT FGQGTKVEIK

[0502] (SEQ ID NO: 148)

[0503] LCDR1 nucleotide sequence

[0504] CAG TCA GTC TCT AGC TCT TAT

[0505] (SEQ ID NO: 149)

[0506] LCDR1 amino acid sequence

[0507] QSVSSSY

[0508] (SEQ ID NO: 150)

[0509] LCDR2 nucleotide sequence

[0510] GGG GCA AGT

[0511] (SEQ ID NO: 151)

[0512] LCDR2 amino acid sequence

[0513] GAS

[0514] (SEQ ID NO: 14)

[0515] LCDR3 nucleotide sequence

[0516] CAA CAG TAC GGA AGC AGC CCG TGG ACG

[0517] (SEQ ID NO: 152)

[0518] LCDR3 amino acid sequence

[0519] QQYGSSPWT

[0520] (SEQ ID NO: 153)

[0521] Heavy chain nucleotide sequence

[0522]

[0523] (SEQ ID NO:154)

[0524] Heavy chain amino acid sequence

[0525] EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIAWVRQMPGKGLEWMGIIYPGDSDTRYSPSFQGQV TMSADKSIRIAYLQWSSLKASDTAMYYCARLDYSGSWFDYWGQGTLVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK*

[0526] (SEQ ID NO:155)

[0527] Light chain nucleotide sequence

[0528] GAAATAGTTTTGACACAGAGTCCCGGCACACTGTCACTCTCTCCCGGGGAAAGAGCCACCTTGTCATGTAGAGCAAGTCAGTCAGTCTCTAGCTCTTATCTCGCCTGGTACCAGCAGAAGCCGGGACAGGCCCCTAGACTGCTGATCTACGGGGCAAGTTCCAGGGCCACCGGAATCCCCGACCGGTTCAGTGGAAGCGGAAGCGGAACCGATTTTACTTTGACGATTTCTAGACTGGAGCCAGAGGATTTCGCCGTTTACTATTGTCAACAGTACGGAAGCAGCCCGTGGACGTTTGGCCAGGGCACGAAGGTAGAAATCAAGCGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG

[0529] (SEQ ID NO:156)

[0530] Light chain amino acid sequence

[0531] EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGS GTDFTLTISRLEPEDFAVYYCQQYGSSPWTFGQGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC*

[0532] (SEQ ID NO:157)

[0533] H4H30108P2

[0534] HCVR nucleotide sequence

[0535] CAGGTCCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTCTGGATACACCTTCAACAGTTATGATGTCAACTGGGTGCGACAGGCCACTGGACAAGGGCTTGAGTGGATGGGATGGATGAACCCTCACAGTGGTAACACAGGCTACGCA CAGAAGTTCCAGGGCAGAGTCACTATGACCAGGGACACCTCCACAAGCACAAGCTATATGGAGTTGAGCAGCCTGACATCTGAGGACACGGCCGTATATTACTGTGCGAGAGGCCCTTTTTCTCTACTTTCAGCTGAATTCTTCCAGCACTGGGGCCAGGGCACCCTGGTCACCGTCTCCTCA

[0536] (SEQ ID NO: 158)

[0537] HCVR amino acid sequence

[0538] QVQLVQSGAEVKKPGASVKVSCKAS GYTFNSYD VNWVRQATGQGLEWMGW MNPHSGNT GYAQKFQGRVTMTRDTSSTSYMELSSLTSEDTAVYYC ARGPFSLLSAEFFQH WGQGTLVTVSS

[0539] (SEQ ID NO: 159)

[0540] HCDR1 nucleotide sequence

[0541] GGA TAC ACC TTC AAC AGT TAT GAT

[0542] (SEQ ID NO: 160)

[0543] HCDR1 amino acid sequence

[0544] GYTFNSYD

[0545] (SEQ ID NO: 161)

[0546] HCDR2 nucleotide sequence

[0547] ATG AAC CCT CAC AGT GGT AAC ACA

[0548] (SEQ ID NO: 162)

[0549] HCDR2 amino acid sequence

[0550] MNPHSGNT

[0551] (SEQ ID NO: 163)

[0552] HCDR3 nucleotide sequence

[0553] GCG AGA GGC CCT TTT TCT CTA CTT TCA GCT GAA TTC TTC CAG CAC (SEQ IDNO:164)

[0554] HCDR3 amino acid sequence

[0555] ARGPFSLLS AE FFQH(SEQ ID NO:165)

[0556] LCVR nucleotide sequence

[0557] GAAATAGTTTTGACACAGAGTCCCGGCACACTGTCACTCTCTCCCGGGGAAAGAGCCACCTTGTCATGTAGAGCAAGTCAGTCAGTCTCTAGCTCTTATCTCGCCTGGTACCAGCAGAAGCCGGGACAGGCCCCTAGACTGCTGATCTACGGGGCAAGTTCC AGGGCCACCGGAATCCCCGACCGGTTCAGTGGAAGCGGAAGCGGAACCGATTTTACTTTGACGATTTCTAGACTGGAGCCAGAGGATTTCGCCGTTTACTATTGTCAACAGTACGGAAGCAGCCCGTGGACGTTTGGCCAGGGCACGAAGGTAGAAATCAAG

[0558] (SEQ ID NO: 147)

[0559] LCVR amino acid sequence

[0560] EIVLTQSPGTLSLSPGERATLSCRAS QSVSSSY LAWYQQKPGQAPRLLIY GAS SRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYC QQYGSSPWT FGQGTKVEIK

[0561] (SEQ ID NO: 148)

[0562] LCDR1 nucleotide sequence

[0563] CAG TCA GTC TCT AGC TCT TAT

[0564] (SEQ ID NO: 149)

[0565] LCDR1 amino acid sequence

[0566] QSVSSSY

[0567] (SEQ ID NO: 150)

[0568] LCDR2 nucleotide sequence

[0569] GGG GCA AGT

[0570] (SEQ ID NO: 151)

[0571] LCDR2 amino acid sequence

[0572] GAS

[0573] (SEQ ID NO: 14)

[0574] LCDR3 nucleotide sequence

[0575] CAA CAG TAC GGA AGC AGC CCG TGG ACG

[0576] (SEQ ID NO: 152)

[0577] LCDR3 amino acid sequence

[0578] QQYGSSPWT

[0579] (SEQ ID NO: 153)

[0580] Heavy chain nucleotide sequence

[0581]

[0582] (SEQ ID NO:166)

[0583] Heavy chain amino acid sequence

[0584] QVQLVQSGAEVKKPGASVKVSCKASGYTFNSYDVNWVRQATGQGLEWMGWMNPHSGNTGYAQKFQGRV TMTRDTSTSTSYMELSSLTSEDTAVYYCARGPFSLLSAEFFQHWGQGTLVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK*

[0585] (SEQ ID NO:167)

[0586] Light chain nucleotide sequence

[0587] GAAATAGTTTTGACACAGAGTCCCGGCACACTGTCACTCTCTCCCGGGGAAAGAGCCACCTTGTCATGTAGAGCAAGTCAGTCAGTCTCTAGCTCTTATCTCGCCTGGTACCAGCAGAAGCCGGGACAGGCCCCTAGACTGCTGATCTACGGGGCAAGTTCCAGGGCCACCGGAATCCCCGACCGGTTCAGTGGAAGCGGAAGCGGAACCGATTTTACTTTGACGATTTCTAGACTGGAGCCAGAGGATTTCGCCGTTTACTATTGTCAACAGTACGGAAGCAGCCCGTGGACGTTTGGCCAGGGCACGAAGGTAGAAATCAAGCGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG

[0588] (SEQ ID NO:156)

[0589] Light chain amino acid sequence

[0590] EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGS GTDFTLTISRLEPEDFAVYYCQQYGSSPWTFGQGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC*

[0591] (SEQ ID NO:157)

[0592] H4H30117P2

[0593] HCVR nucleotide sequence

[0594] CAGGTCCAGCTGGTACAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTCCTCGGTGAAGGTCTCCTGCAAGGCTTCTGGAGACACCTTCAGTAACTATGTTATCGGCTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGAGGGATCATCCCTATCTTTGGTACAACAAACTACGCACAGCAGTTCCAGGGCAGAGTCACGATTACCACGGACGAATCCACGAGCACGGCCTACATGGAGCTGAGCAGCCTGAGATCTGAGGACACGGCCGTGTATTACTGTGCGAGAGATGGGAACTACGGTGACTACTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA

[0595] (SEQ ID NO:168)

[0596] HCVR amino acid sequence

[0597] QVQLVQSGAEVKKPGSSVKVSCKAS GDTFSNYV IGWVRQAPGQGLEWMGG IIPIFGTT NYAQQFQGRVTITTDESTSTAYMELSSLRSEDTAVYYC ARDGNYGDYFDY WGQGTLVTVSS(SEQ ID NO:169)

[0598] HCDR1 nucleotide sequence

[0599] GGA GAC ACC TTC AGT AAC TAT GTT

[0600] (SEQ ID NO:170)

[0601] HCDR1 amino acid sequence

[0602] G D T F S N Y V

[0603] (SEQ ID NO:171)

[0604] HCDR2 nucleotide sequence

[0605] ATC ATC CCT ATC TTT GGT ACA ACA

[0606] (SEQ ID NO: 172)

[0607] HCDR2 amino acid sequence

[0608] I IP IFGTT

[0609] (SEQ ID NO: 173)

[0610] HCDR3 nucleotide sequence

[0611] GCG AGA GAT GGG AAC TAC GGT GAC TAC TTT GAC TAC

[0612] (SEQ ID NO: 174)

[0613] HCDR3 amino acid sequence

[0614] ARDGNYGDYFDY

[0615] (SEQ ID NO: 175)

[0616] LCVR nucleotide sequence

[0617] GAAATAGTTTTGACACAGAGTCCCGGCACACTGTCACTCTCTCCCGGGGAAAGAGCCACCTTGTCATGTAGAGCAAGTCAGTCAGTCTCTAGCTCTTATCTCGCCTGGTACCAGCAGAAGCCGGGACAGGCCCCTAGACTGCTGATCTACGGGGCAAGTTCC AGGGCCACCGGAATCCCCGACCGGTTCAGTGGAAGCGGAAGCGGAACCGATTTTACTTTGACGATTTCTAGACTGGAGCCAGAGGATTTCGCCGTTTACTATTGTCAACAGTACGGAAGCAGCCCGTGGACGTTTGGCCAGGGCACGAAGGTAGAAATCAAG

[0618] (SEQ ID NO: 147)

[0619] LCVR amino acid sequence

[0620] EIVLTQSPGTLSLSPGERATLSCRAS QSVSSSY LAWYQQKPGQAPRLLIY GAS SRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYC QQYGSSPWT FGQGTKVEIK

[0621] (SEQ ID NO: 148)

[0622] LCDR1 nucleotide sequence

[0623] CAG TCA GTC TCT AGC TCT TAT

[0624] (SEQ ID NO: 149)

[0625] LCDR1 amino acid sequence

[0626] QSVSSSY

[0627] (SEQ ID NO: 150)

[0628] LCDR2 nucleotide sequence

[0629] GGG GCA AGT

[0630] (SEQ ID NO: 151)

[0631] LCDR2 amino acid sequence

[0632] GAS

[0633] (SEQ ID NO: 14)

[0634] LCDR3 nucleotide sequence

[0635] CAA CAG TAC GGA AGC AGC CCG TGG ACG

[0636] (SEQ ID NO: 152)

[0637] LCDR3 amino acid sequence

[0638] QQYGSSPWT

[0639] (SEQ ID NO: 153)

[0640] Heavy chain nucleotide sequence

[0641]

[0642] Heavy chain amino acid sequence

[0643] QVQLVQSGAEVKKPGSSVKVSCKASGDTFSNYVIGWVRQAPGQGLEWMGGIIPIFGTTNYAQQFQGRV TITTDESTSTAYMELSSLRSEDTAVYYCARDGNYGDYFDYWGQGTLVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK*

[0644] (SEQ ID NO:177)

[0645] Light chain nucleotide sequence

[0646] GAAATAGTTTTGACACAGAGTCCCGGCACACTGTCACTCTCTCCCGGGGAAAGAGCCACCTTGTCATGTAGAGCAAGTCAGTCAGTCTCTAGCTCTTATCTCGCCTGGTACCAGCAGAAGCCGGGACAGGCCCCTAGACTGCTGATCTACGGGGCAAGTTCCAGGGCCACCGGAATCCCCGACCGGTTCAGTGGAAGCGGAAGCGGAACCGATTTTACTTTGACGATTTCTAGACTGGAGCCAGAGGATTTCGCCGTTTACTATTGTCAACAGTACGGAAGCAGCCCGTGGACGTTTGGCCAGGGCACGAAGGTAGAAATCAAGCGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG

[0647] (SEQ ID NO:156)

[0648] Light chain amino acid sequence

[0649] EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGS GTDFTLTISRLEPEDFAVYYCQQYGSSPWTFGQGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC*

[0650] (SEQ ID NO:157)

[0651] H4H30045P [[ID=第十八条]

[0652] HCVR nucleotide sequence

[0653] CAGGTTCAGCTGGTGCAGTCTGGAGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGACTTCTGGTTACAGATTCGTCAACTATGGTTTCAGCTGGGTGCGCCAGGCCCCTGGACAAGGCCTTGAATGGATGGGATGGATCAGCCCTTATAATGGTAACACAA ACTATATACAGAATCTCCAGGACAGAATCACCATGACCACAGACACCTCTACGAACACAGCCTACATGGAACTGACGAACCTGAGATCTGACGACACGGCCGTAATTACTGTGCGACCTTAACTGGGGTTCACTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA

[0654] (SEQ ID NO: 178)

[0655] HCVR amino acid sequence

[0656] QVQLVQSGAEVKKPGASVKVSCKTS GYRFVNYG FSWVRQAPGQGLEWMGW ISPYNGNT NYIQNLQDRITMTTDTSTNTAYMELTNLRSDDTAVYYC ATLTGVHFDY WGQGTLVTVSS (SEQ ID NO: 179)

[0657] HCDR1 nucleotide sequence

[0658] GGT TAC AGA TTC GTC AAC TAT GGT

[0659] (SEQ ID NO: 180)

[0660] HCDR1 amino acid sequence

[0661] GYRFVNYG

[0662] (SEQ ID NO: 181)

[0663] HCDR2 nucleotide sequence

[0664] ATC AGC CCT TAT AAT GGT AAC ACA

[0665] (SEQ ID NO: 182)

[0666] HCDR2 amino acid sequence

[0667] ISPYNGNT

[0668] (SEQ ID NO: 183)

[0669] HCDR3 nucleotide sequence

[0670] GCG ACC TTA ACT GGG GTT CAC TTT GAC TAC

[0671] (SEQ ID NO: 184)

[0672] HCDR3 amino acid sequence

[0673] ATLTGVHFDY

[0674] (SEQ ID NO: 185)

[0675] LCVR nucleotide sequence

[0676] GCCATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGGGCATTAGAAATGATTTAGGCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAATTCCTGATCTTTGAAACATCTCGTT TACAAAGTGGGGTCCCTTCGAGGTTCAGCGGCAGTGGTTCTGGCACAGATTTCACTCTCACCATCAACAGCCTTCAGCCTGAAGATTTTGCAACTTATTACTGTCTACAAGATTACAATTACCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA

[0677] (SEQ ID NO: 186)

[0678] LCVR amino acid sequence

[0679] AIQMTQSPSSLSASVGDRVTITCRAS QGIRND LGWYQQKPGKAPNLLIF ETS RLQSGVPSRFSGSGSGTDFTLTINSLQPEDFATYYC LQDYNYPWTFGQGTKVEIK

[0680] (SEQ ID NO: 187)

[0681] LCDR1 nucleotide sequence

[0682] CAG GGC ATT AGA AAT GAT

[0683] (SEQ ID NO: 188)

[0684] LCDR1 amino acid sequence

[0685] QGIRND

[0686] (SEQ ID NO: 189)

[0687] LCDR2 nucleotide sequence

[0688] GAA ACA TCT

[0689] (SEQ ID NO: 190)

[0690] LCDR2 amino acid sequence

[0691] ETS

[0692] (SEQ ID NO: 191)

[0693] LCDR3 nucleotide sequence CTACAA GAT TAC AAT TAC CCG TGG ACG

[0694] (SEQ ID NO: 192)

[0695] LCDR3 amino acid sequence

[0696] LQDYNYPWT

[0697] (SEQ ID NO: 193)

[0698] Heavy chain nucleotide sequence

[0699]

[0700] (SEQ ID NO:194)

[0701] Heavy chain amino acid sequence

[0702] QVQLVQSGAEVKKPGASVKVSCKTSGYRFVNYGFSWVRQAPGQGLEWMGWISPYNGNTNYIQNLQDRI TMTTDTSTNTAYMELTNLRSDDTAVYYCATLTGVHFDYWGQGTLVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK*

[0703] (SEQ ID NO:195)

[0704] Light chain nucleotide sequence

[0705] GCCATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGGGCATTAGAAATGATTTAGGCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAATCTCCTGATCTTTGAAACATCTCGTTTACAAAGTGGGGTCCCTTCGAGGTTCAGCGGCAGTGGTTCTGGCACAGATTTCACTCTCACCATCAACAGCCTTCAGCCTGAAGATTTTGCAACTTATTACTGTCTACAAGATTACAATTACCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG

[0706] (SEQ ID NO:196)

[0707] Light chain amino acid sequence

[0708] AIQMTQSPSSSLSASVGDRVTITCRASQGIRNDLGWYQQKPGKAPNLLIFETSRLQSGVPSRFSGSGSG TDFTLTINSLQPEDFATYYCLQDYNYPWTFGQGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC*

[0709] (SEQ ID NO:197)

[0710] H4H30061P

[0711] HCVR nucleotide sequence

[0712] GAGGTGCAGCTGGTGGAGTCTGGGGGGAGGCTTGGCCCAGCCTGGGGGGTCCCTGAAACTCTCTTTGTGAAGCCCTCTGGATTCACGTTCAGTGATTCTGCAATGCACTGGGTCCGCCAGGCTTCCGGAAAAGGGCTGGAGTGGGTTGGTCGTTAGAAGCAGTAGTAAAGC CGACAGGATATGCTGCGTCGGTGAAAGGCAGGTTCACCATCTCCAGATGATTCAAAGAACATGGCGTTTCTGGAAATGAACAGCCTGAAAACCGAAGACACGGCCGTATTACTGTCTCCGAAACTTACGGTGACCCCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTTCA

[0713] (SEQ ID NO:198)

[0714] HCVR

[0715] EVQLVESGGGLAQPGGSLKLSCEAS GFTFSDSA MHWVRQASGKGLEWVGR IRSKANSYAT GYAASVKGRFTISRDDSKNMAFLEMNSLKTEDTAVYYC LRQTYGDP WGQGTLVTVSS(SEQ ID NO:199)

[0716] HCDR1

[0717] GGA TTC ACG TTC AGT GAT TCT GCA

[0718] (SEQ ID NO:200)

[0719] HCDR1

[0720] GFTF SD SA

[0721] (SEQ ID NO:201)

[0722] HCDR2

[0723] ATT AGA AGC AAA GCT AAT AGT TAC GCG ACA

[0724] (SEQ ID NO: 202)

[0725] HCDR2 amino acid sequence

[0726] IRSKANSY AT

[0727] (SEQ ID NO: 203)

[0728] HCDR3 nucleotide sequence

[0729] CTC CGA CAA ACT TAC GGT GAC CCC

[0730] (SEQ ID NO: 204)

[0731] HCDR3 amino acid sequence

[0732] LRQTYGDP

[0733] (SEQ ID NO: 205)

[0734] LCVR nucleotide sequence

[0735] GATGTTGTGATGACTCAGTCTCCACTCTCCCTGTCCGTCACCCTTGCAGCCGGCCTCCATCTCCTGCAGGTCTAGTCTAAGCCTCGTATACAGTGATGGAAACAACTACTGAATTGGTTTCAGCAGAGGCCAGGCCAATCTCCAAGGCGCCTACTTTATAAAGTTTT TAACCGGGACTCTGGGGTCCCAGACAGATTCAGCGGCAGTGGGTCAGGCACTGATTTCACACTGAAAATCAGCAGGGTGGAGGCTGAGGATGTTGGGGTTTATTACTGCATGCAAGGAACACACTGGCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA(SEQ ID NO:206)

[0736] LCVR amino acid sequence

[0737] DVVMTQSPLSLSVTLGQPASISCRSS LSLVYSDGNNY LNWFQQRPGQSPRRLLY KVF NRDSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYC MQGTHWPWTFGQGTKVEIK (SEQ ID NO: 207)

[0738] LCDR1 nucleotide sequence

[0739] CTA AGC CTC GTA TAC AGT GAT GGA AAC AAC TAC

[0740] (SEQ ID NO: 208)

[0741] LCDR1 amino acid sequence

[0742] LSLVY SD GNNY

[0743] (SEQ ID NO: 209)

[0744] LCDR2 nucleotide sequence

[0745] AAA GTT TTT

[0746] (SEQ ID NO:210)

[0747] LCDR2 amino acid sequence

[0748] KVF

[0749] (SEQ ID NO:211)

[0750] LCDR3 nucleotide sequence

[0751] ATG CAA GGA ACA CAC TGG CCG TGG ACG

[0752] (SEQ ID NO:212)

[0753] LCDR3 amino acid sequence

[0754] MQGTHWPWT

[0755] (SEQ ID NO:213)

[0756] Heavy chain nucleotide sequence

[0757]

[0758] (SEQ ID NO:214)

[0759] Heavy chain amino acid sequence

[0760] EVQLVESGGGLAQPGGSLKLSCEASGFTFSDSAMHWVRQASGKGLEWVGRIRSKANSYATGYAASVKG RFTISRDDSKNMAFLEMNSLKTEDTAVYYCLRQTYGDPWGQGTLVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK*

[0761] (SEQ ID NO:215)

[0762] Light chain nucleotide sequence

[0763] GATGTTGTGATGACTCAGTCTCCACTCTCCCTGTCCGTCACCCTTGGACAGCCGGCCTCCATCTCCTGCAGGTCTAGTCTAAGCCTCGTATACAGTGATGGAAACAACTACTTGAATTGGTTTCAGCAGAGGCCAGGCCAATCTCCAAGGCGCCTACTTTATAAAGTTTTTAACCGGGACTCTGGGGTCCCAGACAGATTCAGCGGCAGTGGGTCAGGCACTGATTTCACACTGAAAATCAGCAGGGTGGAGGCTGAGGATGTTGGGGTTTATTACTGCATGCAAGGAACACACTGGCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG

[0764] (SEQ ID NO:216)

[0765] Light chain amino acid sequence

[0766] DVVMTQSPLSLSVTLGQPASISCRSSLSLVYSDGNNYLNWFQQRPGQSPRRLLYKVFNRDSGVPDRFS GSGSGTDFTLKISRVEAEDVGVYYCMQGTHWPWTFGQGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC*

[0767] (SEQ ID NO:217)

[0768] H4H30095P2

[0769] HCVR nucleotide sequence

[0770] CAGGTTCAGCTGGTGCAGTCTGGAGTTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTCTGGTTACACCTTTAAGTTTTATGGTATCAGTTGGGTGCGACAGGCCCTGGACAAGGGCTTGAGTGGATGGGCTGGATCAGTGTTTACAATGGTAAAACAAAGTATGCA CAGAAGCTCCAGGGCAGAGTCACCATGACAACAGACACATCCACGAGCACAGCCTACATGGAGCTGAGGAGCCTGAGATCTGACGACACGGCCGTGTATTTTTGTGCGAGAGATGGGGACTATGAGAGTAGTGGTTATCCGTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA

[0771] (SEQ ID NO:218)

[0772] HCVR amino acid sequence

[0773] QVQLVQSGVEVKKPGASVKVSCKAS GYTFKFYG ISWVRQAPGQGLEWMGW ISVYNGKT KYAQKLQGRVTMTTDTSSTAYMELRSLRSDDTAVYFC ARDGDYESSGYPFDY WGQGTLVTVSS

[0774] (SEQ ID NO:219)

[0775] HCDR1 nucleotide sequence

[0776] GGT TAC ACC TTT AAG TTT TAT GGT

[0777] (SEQ ID NO: 220)

[0778] HCDR1 amino acid sequence

[0779] GYTFKFYG

[0780] (SEQ ID NO:221)

[0781] HCDR2 nucleotide sequence

[0782] ATC AGT GTT TAC AAT GGT AAA ACA

[0783] (SEQ ID NO:222)

[0784] HCDR2 amino acid sequence

[0785] ISVYNGKT

[0786] (SEQ ID NO:223)

[0787] HCDR3 nucleotide sequence

[0788] GCG AGA GAT GGG GAC TAT GAG AGT AGT GGT TAT CCG TTT GAC TAC

[0789] (SEQ ID NO:224)

[0790] HCDR3 amino acid sequence

[0791] ARDGDYESSGYPFDY

[0792] (SEQ ID NO:225)

[0793] LCVR nucleotide sequence

[0794] GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTG CAAAGTGGGGTCCCGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCTCCGATCACCTTCGGCCAAGGGACACGACTGGAGATTAAA

[0795] (SEQ ID NO:226)

[0796] LCVR amino acid sequence

[0797] DIQMTQSPSSLSASVGDRVTITCRAS QSISSY LNWYQQKPGKAPKLLIY AAS SLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYC QQSYSTPPIT FGQGTRLEIK

[0798] (SEQ ID NO:227)

[0799] LCDR1 nucleotide sequence

[0800] CAG AGC ATT AGC AGT TAT

[0801] (SEQ ID NO:31)

[0802] LCDR1 amino acid sequence

[0803] QSISSY

[0804] (SEQ ID NO:32)

[0805] LCDR2 nucleotide sequence

[0806] GCT GCA TCC

[0807] (SEQ ID NO:33)

[0808] LCDR2 amino acid sequence

[0809] AAS

[0810] (SEQ ID NO:34)

[0811] LCDR3 nucleotide sequence

[0812] CAA CAG AGT TAC AGT ACC CCT CCG ATC ACC

[0813] (SEQ ID NO:75)

[0814] LCDR3 amino acid sequence

[0815] QQSYSTPPIT

[0816] (SEQ ID NO:76)

[0817] Heavy chain nucleotide sequence

[0818]

[0819] Heavy chain amino acid sequence

[0820] QVQLVQSGVEVKKPGASVKVSCKASGYTFKFYGISWVRQAPGQGLEWMGWISVYNGKTKYAQKLQGRV TMTTDTSSTAYMELRSLRSDDTAVYFCARDGDYESSGYPFDYWGQGTLVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK*

[0821] (SEQ ID NO:229)

[0822] Light chain nucleotide sequence

[0823] GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCCCGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCACCTTCGGCCAAGGGACACGACTGGAGATTAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG

[0824] (SEQ ID NO:230)

[0825] Light chain amino acid sequence

[0826] DIQMTQSPSSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSG TDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC*

[0827] (SEQ ID NO:231)

[0828] The present invention provides an isolated antibody or antigen-binding fragment thereof that specifically binds to FGFR3 (e.g., monomeric or dimeric human FGFR3b) or an antigenic fragment thereof, the isolated antibody or antigen-binding fragment comprising: a heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of a HCVR comprising the amino acid sequence set forth in SEQ ID NO: 2, 22, 42, 62, 82, 102, 122, 140, 159, 169, 179, 199, or 219 (e.g., fused to an IgG4 Fc having an S108P mutation), and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of a LCVR comprising the amino acid sequence set forth in SEQ ID NO: 10, 30, 50, 70, 90, 110, 130, 148, 187, 207, or 227.

[0829] The present invention also provides an isolated antibody or antigen-binding fragment thereof that specifically binds to FGFR3 (e.g., monomeric or dimeric human FGFR3b) or an antigenic fragment thereof, the isolated antibody or antigen-binding fragment thereof comprising: (a) a heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of a HCVR comprising the amino acid sequence set forth in SEQ ID NO: 2, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of a LCVR comprising the amino acid sequence set forth in SEQ ID NO: 10, (b) a heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of a HCVR comprising the amino acid sequence set forth in SEQ ID NO: 22, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of a LCVR comprising the amino acid sequence set forth in SEQ ID NO: 30, (c) a heavy chain variable region (HCVR) comprising SEQ ID NO: 31. NO:42, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of a LCVR comprising the amino acid sequence set forth in SEQ ID NO:50, (d) a heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of a HCVR comprising the amino acid sequence set forth in SEQ ID NO:62, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of a LCVR comprising the amino acid sequence set forth in SEQ ID NO:70, (e) a heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of a HCVR comprising the amino acid sequence set forth in SEQ ID NO:82, and a light chain variable region (LCVR) comprising SEQ ID NO: NO: 90, (f) a heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of a HCVR comprising the amino acid sequence set forth in SEQ ID NO: 102 (e.g., fused to an IgG4 Fc having an S108P mutation), and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of a LCVR comprising the amino acid sequence set forth in SEQ ID NO: 110, and / or (g) a heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of a HCVR comprising the amino acid sequence set forth in SEQ ID NO: 122,and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of a LCVR comprising the amino acid sequence set forth in SEQ ID NO: 130, (h) a heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of a HCVR comprising the amino acid sequence set forth in SEQ ID NO: 140, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of a LCVR comprising the amino acid sequence set forth in SEQ ID NO: 148, (i) a heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of a HCVR comprising the amino acid sequence set forth in SEQ ID NO: 159, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of a LCVR comprising the amino acid sequence set forth in SEQ ID NO: 148, (j) a heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of a HCVR comprising the amino acid sequence set forth in SEQ ID NO: NO: 169, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of a LCVR comprising the amino acid sequence set forth in SEQ ID NO: 148, (k) a heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of a HCVR comprising the amino acid sequence set forth in SEQ ID NO: 179, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of a LCVR comprising the amino acid sequence set forth in SEQ ID NO: 187, (l) a heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of a HCVR comprising the amino acid sequence set forth in SEQ ID NO: 199, and a light chain variable region (LCVR) comprising SEQ ID NO: NO: 207, and / or (m) a heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of a HCVR comprising the amino acid sequence set forth in SEQ ID NO: 219, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of a LCVR comprising the amino acid sequence set forth in SEQ ID NO: 227.

[0830] The present invention also provides an isolated antibody or antigen-binding fragment thereof that specifically binds to FGFR3 (e.g., monomeric or dimeric human FGFR3b) or an antigenic fragment thereof, the isolated antibody or antigen-binding fragment thereof comprising: (a) a heavy chain variable region comprising a HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 4, a HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 6, and a HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 8, and a light chain variable region comprising a LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 16; (b) a heavy chain variable region comprising a HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 24, a HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 26, and a light chain variable region comprising a LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 16. NO: 28, and a light chain variable region comprising: a LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 32, a LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 34, and a LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 36; (c) a heavy chain variable region comprising: a HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 44, a HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 46, and a HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 48, and a light chain variable region comprising: a LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 52, a LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 54, and a LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 56; (d) a heavy chain variable region comprising: a HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 64, a LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 65, and a LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: a light chain variable region comprising a HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 66 and a HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 68, and a LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 72, a LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 74, and a LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 76;(e) a heavy chain variable region comprising a HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 84, a HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 86, and a HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 88, and a light chain variable region comprising a LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 92, a LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 94, and a LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 96; (f) a heavy chain variable region comprising a HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 104, a HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 106, and a HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 108 (e.g., fused to an IgG4 Fc having an S108P mutation), and a light chain variable region comprising a LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 112, a LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 114, and a LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: NO: 114, and a LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 116; and / or (g) a heavy chain variable region comprising a HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 124, a HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 126, and a HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 128, and a light chain variable region comprising a LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 132, a LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 34, and a LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 134; (h) a heavy chain variable region comprising a HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 142, a HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 144, and a HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 146, and a light chain variable region comprising a HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 150; LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 150, LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 14, and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 153;(i) a heavy chain variable region comprising a HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 161, a HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 163, and a HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 165, and a light chain variable region comprising a LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 150, a LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 153; (j) a heavy chain variable region comprising a HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 171, a HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 173, and a HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 175, and a light chain variable region comprising a LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 150, a LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: (k) a heavy chain variable region comprising a HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 181, a HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 183, and a HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 185, and a light chain variable region comprising a LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 189, a LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 191, and a LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 193; (l) a heavy chain variable region comprising a HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 201, a HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 203, and a HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 205, and a light chain variable region comprising a LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 209, a LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 210, and a LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 211. LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 211 and LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 213;and / or (m) a heavy chain variable region comprising: a HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 221, a HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 223, and a HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 225, and a light chain variable region comprising: a LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 32, a LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 34, and a LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 76.;

[0831] The present invention further provides an isolated antibody or antigen-binding fragment thereof that specifically binds to FGFR3 or an antigenic fragment thereof, the isolated antibody or antigen-binding fragment thereof comprising: a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 2, 22, 42, 62, 82, 102 (e.g., fused to an IgG4 Fc having an S108P mutation), 122, 140, 159, 169, 179, 199 or 219, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 10, 30, 50, 70, 90, 110, 130, 148, 187, 207 or 227.

[0832] In addition, the present invention provides an isolated antibody or antigen-binding fragment thereof, which specifically binds to FGFR3 (e.g., monomeric or dimeric human FGFR3b) or an antigenic fragment thereof, the isolated antibody or antigen-binding fragment thereof comprising: (a) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 2, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 10; (b) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 22, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 30; (c) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 42, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 50; (d) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 62, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 70; (e) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 82, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: NO: 90; (f) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 102, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 110; for example, wherein the heavy chain variable region is fused to an IgG4 Fc having an S108P mutation; (g) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 122, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 130; (h) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 140, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 148; (i) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 159, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 148; (j) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 169, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: (k) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 179, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 187; (l) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 199, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 207; and / or (m) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 219, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 227.

[0833] The present invention provides an isolated antibody or antigen-binding fragment thereof that specifically binds to FGFR3 (e.g., monomeric or dimeric human FGFR3b) or an antigenic fragment thereof, the isolated antibody or antigen-binding fragment thereof comprising: (a) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 18, 38, 58, 78, 98, 118, 136, 155, 167, 177, 195, 215 or 229, and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 20, 40, 60, 80, 100, 120, 138, 157, 197, 217 or 231.

[0834] The present invention also provides an isolated antibody or antigen-binding fragment thereof that specifically binds to FGFR3 or an antigenic fragment thereof, the isolated antibody or antigen-binding fragment thereof comprising:

[0835] (a) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 18, and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 20; (b) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 38, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 40; (c) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 58, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 60; (d) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 78, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 80; (e) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 98, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 100; (f) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 118, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: NO: 120; and / or (g) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 136, and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 138; (h) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 155, and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 157; (i) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 167, and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 157; (j) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 177, and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 157; (k) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 195, and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 197; (l) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 215, and a light chain comprising the amino acid sequence set forth in SEQ ID NO: and / or (m) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 229, and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 231.

[0836] In one embodiment of the present invention, the anti-FGFR3 antigen binding protein (such as an antibody or antigen-binding fragment thereof) has one or more of the following characteristics:

[0837] At 25°C, it binds with an affinity of approximately 16 nM (K D) or greater affinity (e.g., about 16 nM, 12 nM, 10 nM, 7 nM, 5 nM, 4 nM, 3 nM, 2 nM, 1 nM, 0.5 nM, 0.22 nM, 0.2 nM, 0.19 nM, 0.14 nM, 0.1 nM) to monomeric human FGFR3b (e.g., tagged with myc-myc-His6 at the C-terminus) (e.g., in a surface plasmon resonance assay);

[0838] At 25°C, it binds with an affinity of approximately 20 nM (K D ) or greater affinity (e.g., about 20 nM, 16 nM, 15 nM, 10 nM, 8 nM, 5 nM, 4 nM, 3 nM, 2 nM, 1 nM, 0.9 nM, 0.65 nM, 0.3 nM, 0.28 nM, 0.2 nM, 0.15 nM, 0.1 nM) to monomeric cynomolgus monkey FGFR3b (e.g., tagged with myc-myc-His6 at the C-terminus) (e.g., in a surface plasmon resonance assay);

[0839] At 25°C, it binds with an affinity of approximately 70 nM (K D ) or greater affinity (e.g., about 70 nM, 20 nM, 17 nM, 12 nM, 10 nM, 9 nM, 8 nM, 0.1 nM) to monomeric murine FGFR3b (e.g., tagged with myc-myc-His6 at the C-terminus) (e.g., in a surface plasmon resonance assay);

[0840] does not significantly bind to monomeric human FGFR3c (e.g., tagged with myc-myc-His6 at the C-terminus) at 25°C (e.g., in a surface plasmon resonance assay);

[0841] binds to dimeric human FGFR3b (e.g., tagged with mouse Fc (mFc) at the C-terminus) with an affinity of about 0.6 nM or greater (e.g., about 0.58 nM, 0.17 nM, 0.11 nM, 0.04 nM, 0.03 nM, 0.02 nM, 0.01 nM, 0.023 nM, 0.061 nM, 0.031 nM, 0.016 nM, 0.034 nM, 0.027 nM) at 25°C (e.g., in a surface plasmon resonance assay);

[0842] Blocking the binding of FGF1 acidic to human FGFR3b-mFc by about 68% or more (e.g., 90% or 0.5%) at 200 nM of the antibody;

[0843] · To target K binding to monomeric or dimeric human FGFR3b D K values vary by about 0.1 nM DBinds to monomeric cynomolgus monkey and monomeric mouse FGFR3b;

[0844] With an IC of approximately 15nM 50 or lower concentrations (e.g., an IC of about 1 nM, 2 nM, or 3 nM) 50 ) blocks the binding of 4 nM human FGFR3b-mFc to human FGF1 acidic protein;

[0845] competing with another anti-FGFR3 antibody as listed in Table 3-1 herein for binding to hFGFR3b.mmH;

[0846] With an IC of approximately 18 nM 50 Blocking intracellular signaling in an engineered IL-3-dependent Ba / F3 murine hematopoietic cell line genetically modified to stably express wild-type or S249C mutant human fibroblast growth factor receptor 3b (the murine hematopoietic cell line has been stimulated with, e.g., about 5 micrograms / ml of human heparin and, e.g., about 1 nM of human FGF1 ligand) at a concentration of about 100 μg / ml or less (e.g., about 0.51 nM, 0.5 nM, 0.61 nM, 0.6 nM, or 0.012 nM);

[0847] · Lower than the following IC 50 Blocking intracellular signaling in an engineered IL-3-dependent Ba / F3 murine hematopoietic cell line that has been genetically modified to stably express S249C mutant human fibroblast growth factor receptor 3b (the murine hematopoietic cell line has been stimulated with, for example, about 5 micrograms / ml of human heparin and, for example, about 1 nM of human FGF1 ligand): Blocking intracellular signaling in an engineered IL-3-dependent Ba / F3 murine hematopoietic cell line that has been genetically modified to stably express wild-type human fibroblast growth factor receptor 3b (the murine hematopoietic cell line has been stimulated with, for example, about 1 nM of human FGF1 ligand and, for example, about 5 micrograms / ml of human heparin);

[0848] • blocking dimerization of FGFR3 (e.g., wild type or S249C mutant) with greater inhibition than that of REGN6331 as measured, e.g., in a non-reducing SDS-PAGE assay;

[0849] reducing tumor size (e.g., a bladder cancer tumor expressing FGFR3 (e.g., an S249C mutant)) in a subject to which the antibody or fragment is administered;

[0850] reducing CD73 expression in a tumor (e.g., a bladder cancer tumor expressing FGFR3 (e.g., an S249C mutant)) in a subject to which the antibody or fragment is administered;

[0851] Inhibits MAPK phosphorylation induced by FGF1 / heparin stimulation, for example, in BaF3 cells expressing wild-type FGFR3 (e.g., the S249C mutant);

[0852] Inhibits the proliferation of UMUC14 bladder cancer cells expressing the endogenous FGFR3 S249C mutation (e.g., in a cancer cell spheroid proliferation assay);

[0853] Inhibits tumor growth of the bladder cancer cell line UMUC14 expressing FGFR3 (e.g., S249C mutation) in a mouse (e.g., SCID mouse) xenograft model;

[0854] Inhibits CD73-dependent adenosine-mediated suppression of immune cell activation;

[0855] Increase CD8 / CD4 and / or CD8+ / T in tumor tissues harboring tumor cells expressing FGFR3 (e.g., S249C mutant) reg ratio;

[0856] Inhibiting FGF3-mediated activation of CD73 expression and / or enzymatic activity (e.g., adenosine production) (e.g., on tumor cells expressing FGFR3 (e.g., S249C mutant));

[0857] Inhibits FGFR3-dependent adenosine-mediated suppression of immune cells;

[0858] - Inhibiting the growth of BaF3 cells expressing the FGFR3 double mutants S249C and V557M or S249C and V557L, wherein the antibody or antigen-binding fragment comprises an immunoglobulin chain comprising any of the amino acid sequences as set forth herein.

[0859] The present invention includes monoclonal anti-FGFR3 antigen binding proteins, e.g., antibodies and antigen-binding fragments thereof (e.g., H4H30063P; H4H30089P2; H4H30071P; H4H30066P; H4H30102P2; H4H30076P; H4H30105P2; H4H30108P2; H4H30117P2; H4H30045P; H4H30061P; H4H30095P2; or H4H30093P2), as well as monoclonal compositions comprising a plurality of isolated monoclonal antigen binding proteins. As used herein, the term "monoclonal antibody" or "mAb" refers to a member of a substantially homogeneous antibody population, i.e., the antibody molecules comprising the population are identical in amino acid sequence except for possible naturally occurring mutations that may be present in minor amounts. A "plurality" of such monoclonal antibodies and fragments in a composition refers to identical (i.e., in amino acid sequence, except for possible naturally occurring mutations that may be present in minor amounts, as discussed above) antibodies and fragments present at a concentration greater than that which would normally be found in nature (e.g., in the blood of a host organism such as a mouse or human).

[0860] In one embodiment of the invention, the anti-FGFR3 antigen binding protein (e.g., antibody or antigen binding fragment) comprises a heavy chain constant domain of, for example, type IgA (e.g., IgA1 or IgA2), IgD, IgE, IgG (e.g., IgG1, IgG2, IgG3, and IgG4 (e.g., comprising S228P and / or S108P mutations)), or IgM. In one embodiment of the invention, the antigen binding protein (e.g., antibody or antigen binding fragment) comprises a light chain constant domain of, for example, type κ or type λ. The present invention includes proteins comprising V chains listed herein linked to heavy and / or light chain constant domains (e.g., as listed above). H and V L An antigen binding protein comprising a variable domain (e.g., H4H30063P; H4H30089P2; H4H30071P; H4H30066P; H4H30102P2; H4H30076P; H4H30105P2; H4H30108P2; H4H30117P2; H4H30045P; H4H30061P; H4H30095P2; or H4H30093P2).

[0861] As used herein, the term "human" antigen-binding proteins (such as antibodies or antigen-binding fragments) include antibodies and fragments with human amino acid sequences; for example, variable regions and constant regions derived from human germline immunoglobulin sequences, whether in human cells or transplanted into non-human cells (for example, mouse cells). See, for example, US8502018, US6596541 or US5789215. In one embodiment of the invention, the human antibodies and antigen-binding fragments of the present invention may include amino acid residues not encoded by human germline immunoglobulin sequences (for example, with mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutations in vivo), for example, in CDR regions, and particularly in CDR3. However, as used herein, the term "human antibody" is not intended to include mAbs wherein the CDR sequences derived from the germline of another mammalian species (for example, mouse) have been transplanted onto human FR sequences. The term includes antibodies recombinantly produced in non-human mammals or in cells of non-human mammals. The term is not intended to include antibodies separated or produced from human subjects. The present invention includes one or more variable domains of a human antigen binding protein (e.g., an antibody or antigen binding fragment thereof, such as H4H30063P; H4H30089P2; H4H30071P; H4H30066P; H4H30102P2; H4H30076P; H4H30105P2; H4H30108P2; H4H30117P2; H4H30045P; H4H30061P; H4H30095P2; or H4H30093P2).

[0862] The present invention includes anti-FGFR3 chimeric antigen binding proteins, e.g., antibodies and antigen-binding fragments thereof, and methods of using the same. As used herein, a "chimeric antibody" is an antibody having variable domains from a first antibody and constant domains from a second antibody, wherein the first and second antibodies are from different species. (See, e.g., US4816567; and Morrison et al., (1984) Proc. Natl. Acad. Sci. USA 81:6851-6855). The invention includes chimeric antibodies comprising a variable domain listed herein (e.g., from H4H30063P; H4H30089P2; H4H30071P; H4H30066P; H4H30102P2; H4H30076P; H4H30105P2; H4H30108P2; H4H30117P2; H4H30045P; H4H30061P; H4H30095P2; or H4H30093P2) and a non-human constant domain.

[0863] The term "recombinant" antigen-binding protein, such as an antibody or antigen-binding fragment thereof, refers to such molecules formed, expressed, isolated, or obtained by techniques or methods known in the art (e.g., recombinant DNA technology, including, for example, DNA splicing and transgenic expression). The term includes antibodies expressed in a non-human mammal (including a transgenic non-human mammal, e.g., a transgenic mouse) or a host cell (e.g., a Chinese hamster ovary (CHO) cell) or a cell expression system, or isolated from a recombinant combinatorial human antibody library. The present invention includes recombinant antigen binding proteins, such as one or more variable domains of the antibodies and antigen binding fragments listed herein (e.g., H4H30063P; H4H30089P2; H4H30071P; H4H30066P; H4H30102P2; H4H30076P; H4H30105P2; H4H30108P2; H4H30117P2; H4H30045P; H4H30061P; H4H30095P2; or H4H30093P2).

[0864] In one embodiment of the present invention, an antigen-binding fragment of an antibody will contain less than a complete antibody but still specifically binds to an antigen (e.g., FGFR3), for example, comprising at least one variable domain. The variable domain can have any size or amino acid composition and will generally contain at least one (e.g., three) CDRs adjacent to or within a framework with one or more framework sequences. L Domain-associated V H In the antigen-binding fragment of the structural domain, V H and V L The domains can be located in any suitable arrangement relative to each other. For example, the variable region can be dimeric and contain V H -V H 、V H -V L or V L -V L Alternatively, the antigen-binding fragment of an antibody may contain non-covalently bound monomers V H and / or V L domain.

[0865] In certain embodiments, the antigen-binding fragment of an antibody may contain at least one variable domain covalently linked to at least one constant domain. Non-limiting exemplary configurations of variable and constant domains that may be found within the antigen-binding fragment of an antibody of the invention include: (i) V H -CH1;(ii)V H -CH2;(iii)V H -CH3;(iv)V H -CH1-CH2; (v)VH -CH1-CH2-CH3; (vi)V H -CH2-CH3; (vii) V H -CL;(viii)V L -CH1;(ix)V L -CH2;(x)V L -CH3;(xi)V L -CH1-CH2; (xii)VL-CH1-CH2-CH3; (xiii)V L -CH2-CH3; and (xiv) V L -CL. In any configuration of variable and constant domains (including any of the exemplary configurations listed above), the variable and constant domains can be directly connected to each other or can be connected by a complete or partial hinge or linker region. The hinge region can be composed of at least 2 (e.g., 5, 10, 15, 20, 40, 60 or more) amino acids, which results in a flexible or semi-flexible connection between adjacent variable and / or constant domains in a single polypeptide molecule. In addition, the antigen-binding fragments of the antibodies of the present invention may include the above-listed V domains to each other and / or to one or more monomeric V domains. H or V L Homodimers or heterodimers (or other multimers) of any of the variable and constant domain configurations in which the domains are non-covalently associated (e.g., by disulfide bonds). The invention includes antigen-binding fragments of antigen-binding proteins (such as the antibodies listed herein, e.g., H4H30063P; H4H30089P2; H4H30071P; H4H30066P; H4H30102P2; H4H30076P; H4H30105P2; H4H30108P2; H4H30117P2; H4H30045P; H4H30061P; H4H30095P2; or H4H30093P2).

[0866] Antigen binding proteins (e.g., antibodies and antigen binding fragments) can be monospecific or multispecific (e.g., bispecific). Multispecific antigen binding proteins are further discussed herein. The present invention includes monospecific as well as multispecific (e.g., bispecific) antigen binding fragments comprising one or more variable domains from the antigen binding proteins specifically listed herein (e.g., H4H30063P; H4H30089P2; H4H30071P; H4H30066P; H4H30102P2; H4H30076P; H4H30105P2; H4H30108P2; H4H30117P2; H4H30045P; H4H30061P; H4H30095P2; or H4H30093P2).

[0867] In some embodiments, the antigen-binding fragments described herein may be scFvs. ScFvs (single-chain variable region fragments) have heavy chain variable regions (V) preferably bound together by a flexible linker (e.g., a peptide linker). H ) and light chain variable region (V L ) domains (in any order). The length of the flexible linker used to connect the two V regions may be important for producing the correct folding of the polypeptide chain. Previously, it was estimated that a peptide linker must span 3.5 nm between the carboxyl terminus of the variable domain and the amino terminus of the other domain without affecting the ability of the domains to fold and form a complete antigen binding site. (Huston et al., Protein engineering of single-chain Fv analogs and fusion proteins. Methods in Enzymology. 1991; 203: 46–88). In one embodiment, the linker comprises an amino acid sequence of sufficient length to separate the variable domains by approximately 3.5 nm. In one embodiment, the anti-FGFR3 scFv comprises the following variable region arrangement: LCVR-HCVR or HCVR-LCVR, wherein the HCVR and LCVR are optionally connected by a linker.

[0868] In some embodiments, the antigen binding fragment described herein may be a Fab.

[0869] In some embodiments, the antigen-binding fragments described herein can be bivalent antibodies.

[0870] In some embodiments, the anti-FGFR3 antibodies described herein comprise monovalent or "single-arm" antibodies. As used herein, a monovalent or "single-arm" antibody refers to an immunoglobulin comprising a single variable domain. For example, a single-arm antibody can comprise a single variable domain within a Fab, wherein the Fab is connected to at least one Fc fragment. In certain embodiments, the single-arm antibody comprises: (i) a heavy chain comprising a heavy chain constant region and a heavy chain variable region; (ii) a light chain comprising a light chain constant region and a light chain variable region; and (iii) a polypeptide comprising an Fc fragment or a truncated heavy chain. In certain embodiments, the Fc fragment or truncated heavy chain contained in an independent polypeptide is a "pseudo-Fc," which refers to an Fc fragment that is not connected to an antigen binding domain. The single-arm antibodies described herein may comprise any one of the HCVR / LCVR pairs or CDR amino acid sequences listed in Table 1-1 herein. Standard methods can be used to construct a one-armed antibody comprising a full-length heavy chain, a full-length light chain and an additional Fc domain polypeptide (see, for example, WO2010151792, which is incorporated herein by reference in its entirety), wherein the heavy chain constant region differs from the Fc domain polypeptide by at least two amino acids (e.g., H95R and Y96F according to the IMGT exon numbering system; or H435R and Y436F according to the EU numbering system). Such modifications can be used for purification of monovalent antibodies (see WO2010151792).

[0871] The term "specifically binds" or "binds specifically" refers to an antigen (such as a human FGFR3 protein (e.g., FGFR3b isoform), a mouse FGFR3 protein (e.g., FGFR3b isoform), or a cynomolgus monkey FGFR3 protein (e.g., FGFR3b isoform)) that has an expression of at least about 10 -9 M (e.g., 0.01 nM, 0.1 nM, 0.2 nM, 0.3 nM, 0.4 nM, 0.5 nM, 0.6 nM, 0.7 nM, 0.8 nM, 0.9 nM, or 1.0 nM) (as determined, e.g., by real-time label-free biolayer interferometry at 25° C. or 37° C. (e.g., HTX biosensors), or by surface plasmon resonance (e.g., BIACORE TM ), or measured by solution affinity ELISA) D The present invention includes antigen binding proteins that specifically bind to FGFR3 proteins (e.g., FGFR3b isoforms). "Anti-FGFR3" refers to antigen binding proteins (or other molecules), e.g., antibodies or antigen binding fragments thereof, that specifically bind to FGFR3 (e.g., FGFR3b isoforms).

[0872] The invention includes antigen binding proteins, e.g., one or more variable domains of an antibody or antigen binding fragment (e.g., H4H30063P; H4H30089P2; H4H30071P; H4H30066P; H4H30102P2; H4H30076P; H4H30105P2; H4H30108P2; H4H30117P2; H4H30045P; H4H30061P; H4H30095P2; or H4H30093P2) that bind to the same epitope as an antigen binding protein of the invention.

[0873] Antigens are molecules, such as peptides (e.g., FGFR3 or fragments thereof (antigenic fragments)) to which antibodies or their antigen-binding fragments bind. The specific region on an antigen to which an antibody recognizes and binds is referred to as an epitope. Antigen-binding proteins (e.g., antibodies) of the present invention that specifically bind to such antigens are part of the present invention.

[0874] The term "epitope" refers to an antigenic determinant (e.g., on FGFR3b) that interacts with a specific antigen binding site of an antigen-binding protein (e.g., a variable region of an antibody known as a paratope). A single antigen can have more than one epitope. Therefore, different antibodies can bind to different regions on the antigen and can have different biological effects. The term "epitope" can also refer to the site on the antigen to which B and / or T cells respond and / or the antigenic region to which the antibody binds. An epitope can be defined as structural or functional. A functional epitope is typically a subset of a structural epitope and has those residues that directly contribute to the affinity of the interaction. An epitope can be linear or conformational, i.e., composed of nonlinear amino acids. In certain embodiments, an epitope can include a determinant grouped as a chemically active surface of molecules such as amino acids, sugar side chains, phosphoryl or sulfonyl groups, and in certain embodiments, can have specific three-dimensional structural characteristics and / or specific charge characteristics. The epitope to which the antigen-binding protein of the present invention binds can be contained in a fragment (e.g., its extracellular domain) of FGFR3 (e.g., human FGFR3b). Antigen binding proteins (eg, antibodies) of the invention that bind to such epitopes are part of the invention.

[0875] Methods for determining the epitope of an antigen binding protein (e.g., an antibody or fragment or polypeptide) include alanine scanning mutation analysis, peptide blot analysis (Reineke (2004) Methods Mol. Biol. 248: 443-63), peptide cleavage analysis, crystallographic studies, and NMR analysis. In addition, methods such as epitope excision, epitope extraction, and chemical modification of the antigen can be employed (Tomer (2000) Prot. Sci. 9: 487-496). Another method that can be used to identify amino acids within a polypeptide with which an antigen binding protein (e.g., an antibody or fragment or polypeptide) interacts is hydrogen / deuterium exchange detected by mass spectrometry. See, for example, Ehring (1999) Analytical Biochemistry 267: 252-259; Engen and Smith (2001) Anal. Chem. 73: 256A-265A.

[0876] The present invention includes antigen binding proteins that compete with an antigen binding protein of the invention (e.g., H4H30063P; H4H30089P2; H4H30071P; H4H30066P; H4H30102P2; H4H30076P; H4H30105P2; H4H30108P2; H4H30117P2; H4H30045P; H4H30061P; H4H30095P2; or H4H30093P2) for binding to FGFR3 (e.g., an FGFR3b epitope as discussed herein). As used herein, the term "compete" refers to an antigen binding protein (e.g., an antibody or antigen binding fragment thereof) that binds to an antigen (e.g., FGFR3) and inhibits or blocks the binding of another antigen binding protein (e.g., an antibody or antigen binding fragment thereof) to the antigen. Unless otherwise indicated, the term also includes competition between two antigen-binding proteins (e.g., antibodies) in two orientations, that is, the first antibody binds to the antigen and blocks the combination of the second antibody, and vice versa. Therefore, in one embodiment of the invention, competition occurs in such an orientation. In certain embodiments, the first antigen-binding protein (e.g., antibody) and the second antigen-binding protein (e.g., antibody) can be combined with the same epitope. Alternatively, the first antigen-binding protein and the second antigen-binding protein (e.g., antibody) can be combined with different but, for example, overlapping or non-overlapping epitopes, wherein the combination of one suppresses or blocks the combination of the second antibody (e.g., via steric hindrance). Competition between antigen-binding proteins (e.g., antibodies) can be measured by methods known in the art (e.g., by real-time label-free biolayer interferometry). In addition, the binding competition between anti-FGFR3 antigen-binding proteins (e.g., monoclonal antibodies (mAb)) can be determined using real-time label-free biolayer interferometry on Octet RED384 biosensor (Pall ForteBio Corp.).

[0877] Typically, the antibodies or antigen-binding fragments of the present invention are modified in some manner to retain the ability to specifically bind to FGFR3 (e.g., FGFR3b), e.g., to retain at least 10% of their FGFR3 binding activity (when expressed on a molar basis) (when compared to the parental antibody). Preferably, the antibodies or antigen-binding fragments of the present invention retain at least 20%, 50%, 70%, 80%, 90%, 95% or 100% or more of the FGFR3 binding affinity of the parental antibody. It is also intended that the antibodies or antigen-binding fragments of the present invention may contain conservative or non-conservative amino acid substitutions that do not significantly change their biological activity (referred to as "conservative variants" or "function-conservative variants" of antibodies).

[0878] A "variant" of a polypeptide, such as an immunoglobulin chain (e.g., H4H30063P; H4H30089P2; H4H30071P; H4H30066P; H4H30102P2; H4H30076P; H4H30105P2; H4H30108P2; H4H30117P2; H4H30045P; H4H30061P; H4H30095P2; or H4H30093P2) comprising the amino acid sequences specifically set forth herein H 、V L , its HC or LC or CDR), refers to a sequence that contains the same amino acid sequence as the reference amino acid sequence listed herein (e.g., SEQ ID 99, 207, 215, 217, 219, 227, 229, or 231) is at least about 70% to 99.9% (e.g., at least 70%, 72%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 82%, 83%, 84%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 100%, 102%, 110%, 118%, 120%, 122%, 130%, 136%, 138%, 140%, 148%, 155%, 157%, 159%, 167%, 169%, 177%, 179%, 187%, 195%, 197%, 199, 207, 215, 217, 219, 227, 229, or 231) or similar amino acid sequences; (wherein the parameters of the algorithm are selected to maximize matches between the corresponding sequences over the entire length of the corresponding reference sequences (e.g., expect threshold: 10; word length: 3; maximum number of matches in query range: 0; BLOSUM62 matrix; gap cost: existence 11, extension 1; conditional composition score matrix adjustment)).

[0879] In addition, variants of the polypeptide may include, for example, immunoglobulin chains (e.g., H4H30063P; H4H30089P2; H4H30071P; H4H30066P; H4H30102P2; H4H30076P; H4H30105P2; H4H30108P2; H4H30117P2; H4H30045P; H4H30061P; H4H30095P2; or H4H30093P2 V H 、V L, its HC or LC or CDR), which polypeptide can comprise the amino acid sequence of a reference polypeptide whose amino acid sequence is specifically listed herein, but with one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) mutations, for example, one or more missense mutations (e.g., conservative substitutions), nonsense mutations, deletions or insertions. See Table A. For example, the invention includes an anti-FGFR3 antigen binding protein comprising an immunoglobulin light chain (or V chain) comprising the amino acid sequence set forth in SEQ ID NO: 10 but with one or more of such mutations. L ) variants, and / or immunoglobulin heavy chains (or V chains) comprising the amino acid sequence set forth in SEQ ID NO: 2 but having one or more of such mutations H ) variants. In one embodiment of the present invention, the anti-FGFR3 antigen binding protein comprises the following: an immunoglobulin light chain variant comprising CDR-L1, CDR-L2, and CDR-L3, wherein one or more (e.g., 1 or 2 or 3) of such CDRs have one or more of such mutations (e.g., conservative substitutions); and / or an immunoglobulin heavy chain variant comprising CDR-H1, CDR-H2, and CDR-H3, wherein one or more (e.g., 1 or 2 or 3) of such CDRs have one or more of such mutations (e.g., conservative substitutions).

[0880] The following references relate to the BLAST algorithm commonly used for sequence analysis: BLAST ALGORITHMS: Altschul et al. (2005) FEBS J. 272(20):5101-5109; Altschul, SF et al., (1990) J. Mol. Biol. 215:403-410; Gish, W. et al., (1993) Nature Genet. 3:266-272; Madden, TL et al., (1996) Meth. Enzymol. 266:131-141; Altschul, SF et al., (1997) Nucleic Acids Res. 25:3389-3402; Zhang, J. et al., (1997) Genome Res.7:649-656; Wootton, JC et al., (1993) Comput. Chem. 17:149-163; Hancock, JM et al., (1994) Comput. Appl. Biosci. 10:67-70; ALIGNMENT SCORING SYSTEMS: Dayhoff, MO et al., "A model of evolutionary change in proteins." in Atlas of Protein Sequence and Structure, (1978) Vol. 5, Supplement 3. MO Dayhoff (ed.), pp. 345-352, Natl. Biomed. Res. Found., Washington, DC; Schwartz, RM et al., "Matrices for detecting distant relationships.", (1978) Vol. 5, Suppl. 3." MO Dayhoff (ed.), pp. 353-358, Natl. Biomed. Res. Found., Washington, DC; Altschul, SF, (1991) J. Mol. Biol. 219:555-565; States, DJ et al., (1991) Methods 3:66-70; Henikoff, S. et al., (1992) Proc. Natl. Acad. Sci. USA 89:10915-10919; Altschul, SF et al., (1993) J. Mol. Evol. 36:290-300; ALIGNMENT STATISTICS: Karlin, S.et al., (1990) Proc. Natl. Acad. Sci. USA 87:2264-2268; Karlin, S. et al., (1993) Proc. Natl. Acad. Sci. USA 90:5873-5877; Dembo, A. et al., (1994) Ann. Prob. 22:2022-2039; and Altschul, SF "Evaluating the statistical significance of multiple distinct local alignments." in Theoretical and Computational Methods in Genome Research (S. Suhai, ed.), (1997) pp. 1-14, Plenum, NY.

[0881] For example, "conservatively modified variants" or "conservative substitutions" of the immunoglobulin chains listed herein refer to variants in which one or more substitutions of amino acids in the polypeptide are made with other amino acids having similar characteristics (e.g., charge, side chain size, hydrophobicity / hydrophilicity, backbone conformation and rigidity, etc.). Such changes can generally be made without significantly disrupting the biological activity of the antibody or fragment. Those skilled in the art will recognize that, in general, single amino acid substitutions in non-essential regions of a polypeptide will not significantly alter biological activity (see, e.g., Watson et al. (1987) Molecular Biology of the Gene, The Benjamin / Cummings Pub. Co., p. 224 (4th ed.)). Furthermore, substitutions of structurally or functionally similar amino acids are unlikely to significantly disrupt biological activity. The present invention includes anti-FGFR3 antigen-binding proteins comprising such conservatively modified variant immunoglobulin chains.

[0882] Examples of amino acid groups with side chains of similar chemical properties include: 1) aliphatic side chains: glycine, alanine, valine, leucine, and isoleucine; 2) aliphatic hydroxyl side chains: serine and threonine; 3) amide-containing side chains: asparagine and glutamine; 4) aromatic side chains: phenylalanine, tyrosine, and tryptophan; 5) basic side chains: lysine, arginine, and histidine; 6) acidic side chains: aspartic acid and glutamic acid; and 7) sulfur-containing side chains: cysteine and methionine. Alternatively, a conservative substitution is any change that has a positive value in the PAM250 log-likelihood matrix disclosed in Gonnet et al. (1992) Science 256:1443-45.

[0883] Unless otherwise indicated, “H4H30063P” (“REGN15684”); “H4H30066P”; “H4H30071P”; “H4H30089P2”; “H4H30093P2”; “H4H30102P2”; “H4H30076P”; “H4H30105P2”; “H4H30108P2”; “H4H30117P2”; “H4H30045P”; “H4H30061P”; and “H4H30095P2” refer to anti-FGFR3 antigen binding proteins, e.g., antibodies and antigen-binding fragments thereof (including multispecific antigen-binding proteins), comprising an immunoglobulin heavy chain variable region (V4H30061P) comprising the amino acid sequence pairs specified in the following items as listed in Table A. H ) and immunoglobulin light chain variable region (V L ):SEQ ID NO:2 and 10; 22 and 30; 42 and 50; 62 and 70; 82 and 90; 102 and 110; 122 and 130; 140 and 148; 159 and 148; 169 and 148; 179 and 187; 199 and 207; and 219 and 227 (or variants of any of said sequences); or comprising an immunoglobulin heavy chain (HC) and an immunoglobulin light chain (LC) comprising the amino acid sequence pairs specified in the following items as listed in Table A: SEQ ID NO: NO: 18 and 20; 38 and 40; 58 and 60; 78 and 80; 98 and 100; 118 and 120; 136 and 138; 155 and 157; 167 and 157; 177 and 157; 195 and 197; 215 and 217; or 229 and 231 (or variants of any of said sequences); or comprising the following: a heavy chain or V chain comprising its CDRs H (CDR-H1 (or its variant), CDR-H2 (or its variant) and CDR-H3 (or its variant)), and / or a light chain or V chain comprising its CDRs L (CDR-L1 (or its variant), CDR-L2 (or its variant) and CDR-L3 (or its variant)). In one embodiment of the present invention, V H is linked to an IgG constant heavy chain domain, e.g., a human IgG constant heavy chain domain (e.g., IgG1 or IgG4 (e.g., comprising S228P and / or S108P mutations)), and / or V L is linked to a light chain constant domain, e.g., a human light chain constant domain (e.g., a lambda or kappa constant light chain domain). Encoding any such immunoglobulin chain (e.g., V H 、V L , HC and / or LC) form part of the present invention.

[0884] The antibodies and antigen-binding fragments of the invention (e.g., H4H30063P; H4H30089P2; H4H30071P; H4H30066P; H4H30102P2; H4H30076P; H4H30105P2; H4H30108P2; H4H30117P2; H4H30045P; H4H30061P; H4H30095P2; or H4H30093P2) comprise immunoglobulin chains comprising the amino acid sequences specifically listed herein (and variants thereof) as well as cellular and in vitro post-translational modifications to the antibodies or fragments. For example, the present invention includes antibodies and antigen-binding fragments thereof that specifically bind to FGFR3, comprising the heavy and / or light chain amino acid sequences, and antibodies and fragments thereof, listed herein, wherein one or more asparagine, serine and / or threonine residues are glycosylated, one or more asparagine residues are deamidated, one or more residues (e.g., Met, Trp and / or His) are oxidized, the N-terminal glutamine is replaced by pyroglutamic acid (pyroE) and / or the C-terminal lysine or other amino acids are deleted.

[0885] The invention provides a container (e.g., a plastic or glass vial (e.g., with a cap or chromatography column), a hollow bore needle, or a syringe barrel) comprising an anti-FGFR3 antigen binding protein of the invention, e.g., H4H30063P; H4H30089P2; H4H30071P; H4H30066P; H4H30102P2; H4H30076P; H4H30105P2; H4H30108P2; H4H30117P2; H4H30045P; H4H30061P; H4H30095P2; or H4H30093P2.

[0886] The present invention also provides an injection device comprising one or more antigen-binding proteins (e.g., antibodies or antigen-binding fragments) that specifically bind to FGFR3 (e.g., H4H30063P; H4H30089P2; H4H30071P; H4H30066P; H4H30102P2; H4H30076P; H4H30105P2; H4H30108P2; H4H30117P2; H4H30045P; H4H30061P; H4H30095P2; or H4H30093P2) or a pharmaceutical formulation thereof. The injection device can be packaged into a kit. The injection device is a device for introducing a substance into a subject via a parenteral route (e.g., intraocular, intravitreal, intramuscular, subcutaneous, or intravenous). For example, the injection device can be a syringe or autoinjector (e.g., pre-filled with a pharmaceutical formulation), which includes, for example, a barrel or cartridge for holding a fluid to be injected (e.g., comprising an antibody or fragment or a pharmaceutical formulation thereof), a needle for piercing the skin, a blood vessel, or other tissue to inject the fluid; and a plunger for pushing the fluid out of the barrel and through the needle aperture and into the subject's body.

[0887] Post-translational modification

[0888] The anti-FGFR3 antibodies and antigen-binding fragments of the invention may be modified post-translationally, for example, by glycosylation.

[0889] For example, the antibodies and antigen-binding fragments of the present invention can be glycosylated (e.g., N-glycosylated and / or O-glycosylated) or non-glycosylated. Typically, antibodies and antigen-binding fragments are glycosylated at the conserved residue N297 of the IgG Fc domain. Some antibodies and fragments contain one or more additional glycosylation sites in the variable region. In one embodiment of the present invention, the glycosylation site is in the following context: FN 297 S or YN 297 S.

[0890] In one embodiment of the present invention, the glycosylation is any one or more of the three different N-glycan types found on IgG with their corresponding linkage patterns: high mannose, complex, and / or mixed. Complex and mixed types exist as core fucosylation (i.e., addition of fucose residues to the innermost N-acetylglucosamine) and no core fucosylation.

[0891] In one embodiment of the present invention, the antibodies or fragments of the present invention are non-fucosylated. Some IgG1 antibodies rely on Fc-mediated immune effector function (antibody-dependent cellular cytotoxicity (ADCC)) as a primary mode of action for depleting tumor cells. This effector function is regulated by N-linked glycosylation in the Fc region of the antibody. In particular, the absence of core fucose on Fc N-glycans has been shown to increase the binding affinity of IgG1 Fc to FcγRIIIa present on immune effector cells (such as natural killer cells) and lead to enhanced ADCC activity.

[0892] The antibodies and antigen-binding fragments of the invention may also be post-translationally modified by other means, including, for example: Glu or Gln cyclization at the N-terminus; loss of positive N-terminal charge; Lys variants at the C-terminus; deamidation (Asn to Asp); isomerization (Asp to isoAsp); deamidation (Gln to Glu); oxidation (Cys, His, Met, Tyr, Trp); and / or disulfide bond heterogeneity (shuffling, thioether and trisulfide bond formation).

[0893] Polynucleotides and preparation methods

[0894] Polynucleotides include DNA and RNA. The present invention includes any polynucleotide of the present invention, for example, encoding an immunoglobulin V H 、V L, CDR-H, CDR-L, HC or LC polynucleotides: H4H30063P; H4H30089P2; H4H30071P; H4H30066P; H4H30102P2; H4H30076P; H4H30105P2; H4H30108P2; H4H30117P2; H4H30045P; H4H30061P; H4H30095P2; and / or H4H30093P2, optionally operably linked to a promoter or other expression control sequence. For example, the present invention provides any polynucleotide (e.g., DNA) comprising the nucleotide sequence listed in SEQ ID NO: NO:1;3;5;7;9;11;13;15;17;19;21;23;25;27;29;31;33;35;37;39;41;43;45;47;49;51;53;55;57;59;61;63;65;67;69; 71;73;75;77;79;81;83;85;87;89;91;93;95;97;99;101;103;105;107;109;111;113;115;117;119;121;123;125;127;12 or 230. In one embodiment of the invention, the polynucleotides of the invention are fused to a secretory signal sequence. Polypeptides encoded by such polynucleotides are also within the scope of the invention.

[0895] Generally speaking, a "promoter" or "promoter sequence" is a DNA regulatory region that is capable of binding to RNA polymerase in a cell (e.g., directly or through other promoter-binding proteins or substances) and initiating transcription of a coding sequence. The promoter can be operably linked to other expression control sequences (including enhancer and repressor sequences) and / or to the polynucleotides of the present invention. Promoters that can be used to control gene expression include, but are not limited to, the cytomegalovirus (CMV) promoter (U.S. Pat. Nos. 5,385,839 and 5,168,062), the SV40 early promoter region (Benoist et al., (1981) Nature 290:304-310), the promoter contained in the 3' long terminal repeat of Rous sarcoma virus (Yamamoto et al., (1980) Cell 22:787-797), the herpes thymidine kinase promoter (Wagner et al., (1981) Proc. Natl. Acad. Sci. USA 78:1441-1445), the regulatory sequence of the metallothionein gene (Brinster et al., (1982) Nature 296:39-42); prokaryotic expression mediators such as the β-lactamase promoter (VIIIa-Komaroff et al., (1978) Proc. Natl. Acad. Sci. USA 75:3727-3731) or tac promoter (DeBoer et al., (1983) Proc. Natl. Acad. Sci. USA 80:21-25); see also "Useful proteins from recombinant bacteria" in Scientific American (1980) 242:74-94; and promoter elements from yeast or other fungi, such as the Gal4 promoter, ADC (alcohol dehydrogenase) promoter, PGK (phosphoglycerol kinase) promoter, or alkaline phosphatase promoter.

[0896] A polynucleotide encoding a polypeptide is "operably linked" to a promoter or other expression control sequence when, in a cell or other expression system, the sequence directs RNA polymerase-mediated transcription of the coding sequence into RNA (preferably mRNA), which can then be spliced (if it contains introns) and optionally translated into the protein encoded by the coding sequence.

[0897] The present invention includes a polynucleotide comprising a polynucleotide encoding V H and V L The following polynucleotide pairs:

[0898] SEQ ID NO: 1 and SEQ ID NO: 9;

[0899] SEQ ID NO: 21 and SEQ ID NO: 29;

[0900] SEQ ID NO:41 and SEQ ID NO:49;

[0901] SEQ ID NO:61 and SEQ ID NO:69;

[0902] SEQ ID NO:81 and SEQ ID NO:89;

[0903] SEQ ID NO: 101 and SEQ ID NO: 109;

[0904] SEQ ID NO: 121 and SEQ ID NO: 129;

[0905] SEQ ID NO: 139 and SEQ ID NO: 147;

[0906] SEQ ID NO: 158 and SEQ ID NO: 147;

[0907] SEQ ID NO: 168 and SEQ ID NO: 147;

[0908] SEQ ID NO: 178 and SEQ ID NO: 186;

[0909] SEQ ID NO: 198 and SEQ ID NO: 206; and / or

[0910] SEQ ID NO: 218 and SEQ ID NO: 226;

[0911] or two separate polynucleotides, each comprising one of the following sequences

[0912] SEQ ID NO: 1 and SEQ ID NO: 9;

[0913] SEQ ID NO: 21 and SEQ ID NO: 29;

[0914] SEQ ID NO:41 and SEQ ID NO:49;

[0915] SEQ ID NO:61 and SEQ ID NO:69;

[0916] SEQ ID NO:81 and SEQ ID NO:89;

[0917] SEQ ID NO: 101 and SEQ ID NO: 109

[0918] SEQ ID NO: 121 and SEQ ID NO: 129;

[0919] SEQ ID NO: 139 and SEQ ID NO: 147;

[0920] SEQ ID NO: 158 and SEQ ID NO: 147;

[0921] SEQ ID NO: 168 and SEQ ID NO: 147;

[0922] SEQ ID NO: 178 and SEQ ID NO: 186;

[0923] SEQ ID NO: 198 and SEQ ID NO: 206; or

[0924] SEQ ID NO:218 and SEQ ID NO:226.

[0925] The present invention includes a polynucleotide comprising the following set of polynucleotides encoding CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3:

[0926] SEQ ID NO: 3, 5, 7, 11, 13 and 15;

[0927] SEQ ID NO: 23, 25, 27, 31, 33 and 35;

[0928] SEQ ID NO: 43, 45, 47, 51, 53 and 55;

[0929] SEQ ID NO: 63, 65, 67, 71, 73 and 75;

[0930] SEQ ID NOs: 83, 85, 87, 91, 93 and 95;

[0931] SEQ ID NO: 103, 105, 107, 111, 113 and 115;

[0932] SEQ ID NO: 123, 125, 127, 131, 33 and 133;

[0933] SEQ ID NO: 141, 143, 415, 149, 151 and 152;

[0934] SEQ ID NO: 160, 162, 164, 149, 151 and 152;

[0935] SEQ ID NO: 170, 172, 174, 149, 151 and 152;

[0936] SEQ ID NOs: 180, 182, 184, 188, 190 and 192;

[0937] SEQ ID NO: 200, 202, 204, 208, 210 and 212; and / or

[0938] SEQ ID NO: 220, 222, 224, 31, 33 and 75;

[0939] or two separate polynucleotides, each comprising one of the following sequences

[0940] SEQ ID NO: 3, 5 and 7; and 11, 13 and 15;

[0941] SEQ ID NO: 23, 25 and 27; and 31, 33 and 35;

[0942] SEQ ID NO: 43, 45 and 47; and 51, 53 and 55;

[0943] SEQ ID NO: 63, 65 and 67; and 71, 73 and 75;

[0944] SEQ ID NOs: 83, 85 and 87; and 91, 93 and 95;

[0945] SEQ ID NO: 103, 105 and 107; and 111, 113 and 115;

[0946] SEQ ID NO: 123, 125 and 127; 131, 33 and 133;

[0947] SEQ ID NO: 141, 143 and 415; 149, 151 and 152;

[0948] SEQ ID NO: 160, 162 and 164; 149, 151 and 152;

[0949] SEQ ID NO: 170, 172 and 174; 149, 151 and 152;

[0950] SEQ ID NO: 180, 182 and 184; 188, 190 and 192;

[0951] SEQ ID NO: 200, 202 and 204; 208, 210 and 212; or

[0952] SEQ ID NO: 220, 222 and 224; 31, 33 and 75.

[0953] The present invention includes a polynucleotide comprising the following polynucleotide pair encoding HC and LC:

[0954] SEQ ID NO: 17 and SEQ ID NO: 19;

[0955] SEQ ID NO:37 and SEQ ID NO:39;

[0956] SEQ ID NO:57 and SEQ ID NO:59;

[0957] SEQ ID NO:77 and SEQ ID NO:79;

[0958] SEQ ID NO:97 and SEQ ID NO:99;

[0959] SEQ ID NO: 117 and SEQ ID NO: 119;

[0960] SEQ ID NO: 135 and SEQ ID NO: 137;

[0961] SEQ ID NO: 154 and SEQ ID NO: 156;

[0962] SEQ ID NO: 166 and SEQ ID NO: 156;

[0963] SEQ ID NO: 176 and SEQ ID NO: 156;

[0964] SEQ ID NO: 194 and SEQ ID NO: 196;

[0965] SEQ ID NO: 214 and SEQ ID NO: 216; and / or

[0966] SEQ ID NO: 228 and SEQ ID NO: 230;

[0967] or two separate polynucleotides, each comprising one of the following sequences

[0968] SEQ ID NO: 17 and SEQ ID NO: 19;

[0969] SEQ ID NO:37 and SEQ ID NO:39;

[0970] SEQ ID NO:57 and SEQ ID NO:59;

[0971] SEQ ID NO:77 and SEQ ID NO:79;

[0972] SEQ ID NO:97 and SEQ ID NO:99;

[0973] SEQ ID NO: 117 and SEQ ID NO: 119;

[0974] SEQ ID NO: 135 and SEQ ID NO: 137;

[0975] SEQ ID NO: 154 and SEQ ID NO: 156;

[0976] SEQ ID NO: 166 and SEQ ID NO: 156;

[0977] SEQ ID NO: 176 and SEQ ID NO: 156;

[0978] SEQ ID NO: 194 and SEQ ID NO: 196;

[0979] SEQ ID NO: 214 and SEQ ID NO: 216; and / or

[0980] SEQ ID NO:228 and SEQ ID NO:230.

[0981] Host cells containing two separate polynucleotides as discussed above, each integrated into a different locus or ectopically in the host cell chromosomal DNA, wherein such polynucleotides are maintained in separate genetic elements, are within the scope of the present invention.

[0982] The present invention includes polynucleotides encoding immunoglobulin polypeptide chains that are variants of those whose nucleotide sequences are specifically listed herein. A "variant" of a polynucleotide refers to a polynucleotide comprising a nucleotide sequence that is at least about 70% to 99.9% (e.g., 70%, 72%, 74%, 75%, 76%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%) identical to a reference nucleotide sequence listed herein; (wherein the parameters of the algorithm are selected to maximize matching between the corresponding sequences over the entire length of the corresponding reference sequence (e.g., expect threshold: 10; word length: 28; maximum number of matches within query range: 0; match / mismatch score: 1, -2; gap cost: linear)). In one embodiment of the invention, variants of the nucleotide sequences specifically listed herein comprise one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) point mutations, insertions (e.g., in-frame insertions), or deletions (e.g., in-frame deletions) of one or more nucleotides. In one embodiment of the invention, such mutations may be missense mutations or nonsense mutations. In one embodiment of the invention, such variant polynucleotides encode immunoglobulin polypeptide chains that can be incorporated into anti-FGFR3 antigen binding proteins, i.e., such that the protein retains specific binding to FGFR3.

[0983] Eukaryotic and prokaryotic host cells (including mammalian cells) can be used as hosts for expressing anti-FGFR3 antigen-binding proteins (e.g., antibodies or their antigen-binding fragments). Such host cells are well known in the art, and many are available from the American Type Culture Collection (ATCC). These host cells particularly include Chinese hamster ovary (CHO) cells, NSO, SP2 cells, HeLa cells, baby hamster kidney (BHK) cells, monkey kidney cells (COS), human hepatocellular carcinoma cells (e.g., HepG2), A549 cells, 3T3 cells, HEK-293 cells, and many other cell lines. Mammalian host cells include humans, mice, rats, dogs, monkeys, pigs, goats, cattle, horses, and hamster cells. Other cell lines that can be used are insect cell lines (e.g., fall armyworm (Spodoptera frugiperda) or cabbage looper (Trichoplusia ni)), amphibian cells, bacterial cells, plant cells, and fungal cells.Fungal cells include yeast and filamentous fungal cells, including, for example, Pichia, Pichia pastoris, Pichia finlandica, Pichia trehalophila, Pichia koclamae, Pichia membranaefaciens, Pichia minuta (Ogataea minuta, Pichia alindneri), Pichia opuntiae, Pichia athermotolerans, Pichia salictaria, Pichia guercuum, Pichia pijperi, Pichia stiptis, Pichia methanolica, Pichia spp. sp.), Saccharomyces cerevisiae, Saccharomyces sp., Hansenula polymorpha, Kluyveromyces sp., Kluyveromyces lactis, Candida albicans, Aspergillus nidulans, Aspergillus niger, Aspergillus oryzae, Trichoderma reesei, Chrysosporium lucknowense, Fusarium sp., Fusarium gramineum, Fusarium venenatum, Physcomitrella patens, and Neurospora crassa. The present invention includes an isolated host cell (eg, a CHO cell or any of the types of host cells listed above) comprising an antigen binding protein, V thereof. H 、V L, HC, LC or CDR (or variants thereof), such as H4H30063P; H4H30089P2; H4H30071P; H4H30066P; H4H30102P2; H4H30076P; H4H30105P2; H4H30108P2; H4H30117P2; H4H30045P; H4H30061P; H4H30095P2; or H4H30093P2; and / or polynucleotides encoding one or more immunoglobulin chains thereof (e.g., as discussed herein). In one embodiment of the invention, the host cell comprises two separate polynucleotides, one encoding a V H , and another code V L ; or one encodes HC and the other encodes LC.

[0984] The invention also includes cells that express FGFR3 or an antigenic fragment or fusion thereof (e.g., His6 (SEQ ID NO: 235), Fc (e.g., mouse Fc (mFc)), myc or mycmycHis6 (mmh)) that is bound by an antigen binding protein (e.g., an antibody or antigen binding fragment thereof) of the invention, e.g., H4H30063P; H4H30089P2; H4H30071P; H4H30066P; H4H30102P2; H4H30076P; H4H30105P2; H4H30108P2; H4H30117P2; H4H30045P; H4H30061P; H4H30095P2; or H4H30093P2, e.g., wherein the cell is in a subject in vivo or in vitro. In addition, the present invention also provides a complex comprising an anti-FGFR3 antigen binding protein (e.g., an antibody or antigen-binding fragment thereof) as discussed herein, complexed with an FGFR3 polypeptide, an antigenic fragment thereof, or a fusion thereof, and / or complexed with a second antibody or antigen-binding fragment thereof that specifically binds to the anti-FGFR3 antibody or fragment (e.g., a detectably labeled second antibody). In one embodiment of the invention, the complex is in vitro (e.g., immobilized to a solid substrate) or in vivo in a subject.

[0985] In one embodiment of the present invention, the myc tag has the amino acid sequence EQKLISEEDLGG (SEQ ID NO: 234), His6 (SEQ ID NO: 235), or hexahis (SEQ ID NO: 235), or the hexahistidine (SEQ ID NO: 235) tag has the amino acid sequence HHHHHH (SEQ ID NO: 235), and the mmh tag has the amino acid sequence EQKLISEEDLGGEQKLISEEDLHHHHHH (SEQ ID NO: 236). NO: 236), and the mouse Fc tag has the amino acid sequence EPRGPTIKPCPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGK (SEQ ID NO: 237).

[0986] The recombinant anti-FGFR3 antigen binding proteins (e.g., antibodies and antigen binding fragments) disclosed herein can also be produced in the E. coli / T7 expression system. In this embodiment, the polynucleotide encoding the anti-FGFR3 antibody immunoglobulin molecule of the present invention (e.g., its HC, LC, V H and / or V Lor CDRs (H4H30063P; H4H30089P2; H4H30071P; H4H30066P; H4H30102P2; H4H30076P; H4H30105P2; H4H30108P2; H4H30117P2; H4H30045P; H4H30061P; H4H30095P2; or H4H30093P2) can be inserted into a pET-based plasmid and expressed in the E. coli / T7 system. For example, the present invention includes a method for expressing an antibody or antigen-binding fragment thereof or an immunoglobulin chain thereof in a host cell (e.g., a bacterial host cell, such as Escherichia coli (E. coli), such as BL21 or BL21DE3), the method comprising: expressing T7 RNA polymerase in the cell, the cell further comprising a polynucleotide encoding an immunoglobulin chain operably linked to a T7 promoter (e.g., comprising a nucleotide sequence in any one or more of SEQ ID NOs: 1, 3, 5, 7, 9, 11, 13, 15, 17, or 19; or a variant thereof). For example, in one embodiment of the invention, a bacterial host cell (such as E. coli) comprises a polynucleotide encoding a T7 RNA polymerase gene operably linked to a lac promoter, and expression of the polymerase and the chain is induced by incubating the host cell with IPTG (isopropyl-β-D-thiogalactopyranoside). See US4952496 and US5693489 or Studier & Moffatt, Use of bacteriophage T7 RNA polymerase to direct selective high-level expression of cloned genes, J. Mol. Biol. 1986 May 5; 189(1): 113-30.

[0987] There are several methods known in the art by which recombinant antibodies are produced. One example of a method for the recombinant production of antibodies is disclosed in US4816567.

[0988] Transformation can be performed by any known method for introducing a polynucleotide into a host cell. Methods for introducing heterologous polynucleotides into mammalian cells are well known in the art and include dextran-mediated transfection, calcium phosphate precipitation, polybrene-mediated transfection, protoplast fusion, electroporation, encapsulation of the polynucleotide in liposomes, biolistic injection, and direct microinjection of DNA into the nucleus. In addition, nucleic acid molecules can be introduced into mammalian cells via viral vectors. Methods for transforming cells are well known in the art. See, for example, U.S. Patent Nos. 4,399,216; 4,912,040; 4,740,461 and 4,959,455. Therefore, the present invention includes a recombinant method for preparing an anti-FGFR3 (e.g., monomeric or dimeric FGFR3b) antigen binding protein (such as an antibody of the invention or an antigen-binding fragment thereof; or an immunoglobulin chain thereof) comprising (i) introducing into a host cell one or more polynucleotides (e.g., comprising SEQ ID NO: 100). NO: 1, 9, 17 and / or 19 in any one or more of the nucleotide sequence; or a variant thereof), the one or more polynucleotides encoding the light and / or heavy immunoglobulin chain of the antigen binding protein, for example, H4H30063P; H4H30089P2; H4H30071P; H4H30066P; H4H30102P2; H4H30076P; H4H30105P2; H4H30108P2; H4H 30117P2; H4H30045P; H4H30061P; H4H30095P2; or H4H30093P2, e.g., wherein the polynucleotide is in a mediator; and / or integrated into the host cell chromosome and / or operably linked to a promoter; (ii) culturing the host cells (e.g., CHO or Pichia or Pichia pastoris) under conditions conducive to expression of the polynucleotide, and (iii) optionally, isolating the antigen binding protein (e.g., antibody or antigen binding fragment) or chain from the host cells and / or the culture medium in which the host cells are grown. When preparing an antigen-binding protein (e.g., an antibody or antigen-binding fragment) comprising more than one immunoglobulin chain, for example, an antibody comprising two heavy immunoglobulin chains and two light immunoglobulin chains, if such chains are secreted, co-expression of the chains in a single host cell causes the chains to associate, for example, in the cell or on the cell surface or outside the cell, to form the antigen-binding protein (e.g., antibody or antigen-binding fragment). The methods of the present invention include those in which only heavy immunoglobulin chains, or only light immunoglobulin chains, or both (e.g., any of those comprising mature fragments and / or variable domains thereof discussed herein) are expressed in the cell. Such single chains can be used, for example, as intermediates in the expression of antibodies or antigen-binding fragments comprising such chains.For example, the present invention also encompasses anti-FGFR3 antigen binding proteins, such as antibodies and antigen-binding fragments thereof, that are the product of the preparation methods outlined herein and, optionally, the purification methods outlined herein.

[0989] In one embodiment of the invention, a method for preparing an anti-FGFR3 (e.g., monomeric or dimeric FGFR3b) antigen binding protein (e.g., an antibody or antigen-binding fragment thereof) includes a method for purifying the antigen binding protein, e.g., by column chromatography, precipitation, and / or filtration. As discussed, the products of such methods also form part of the present invention.

[0990] Preparation of human antibodies

[0991] The anti-FGFR3 (e.g., monomeric or dimeric FGFR3b) antibodies and antigen-binding fragments of the present invention (e.g., H4H30063P; H4H30089P2; H4H30071P; H4H30066P; H4H30102P2; H4H30076P; H4H30105P2; H4H30108P2; H4H30117P2; H4H30045P; H4H30061P; H4H30095P2; or H4H30093P2) can be fully human antibodies and fragments. Methods for producing monoclonal antibodies, including fully human monoclonal antibodies, are known in the art. Any such known methods can be used in the context of the present invention to prepare human antibodies that specifically bind to human FGFR3.

[0992] For example, using VELOCIMMUNE TM The present invention relates to a method for producing a fully human monoclonal antibody, wherein the antibody is characterized and screened for desirable characteristics (including affinity, ligand blocking activity, selectivity, epitope, etc.) using a human variable region and a mouse constant region. If necessary, the mouse constant region is replaced with a desired human constant region (e.g., wild-type or modified IgG1 or IgG4) to generate a fully human anti-FGFR3 antibody. Although the selected constant region can vary according to specific use, high-affinity antigen binding and target-specific properties are present in the variable region. In some cases, fully human anti-FGFR3 antibodies are isolated directly from antigen-positive B cells. See, for example, US6596541, Regeneron Pharmaceuticals,

[0993] Anti-FGFR3 antibodies including Fc variants

[0994] According to certain embodiments of the present invention, anti-FGFR3 (e.g., monomeric or dimeric FGFR3b) antibodies and antigen-binding fragments (e.g., H4H30063P; H4H30089P2; H4H30071P; H4H30066P; H4H30102P2; H4H30076P; H4H30105P2; H4H30108P2; H4H30117P2; H4H30045P; H4H30061P; H4H30095P2; or H4H30093P2) are provided that comprise an Fc domain. The domain comprises one or more mutations that enhance or reduce the binding of the antibody to the FcRn receptor at acidic pH, such as compared to neutral pH (e.g., H4H30063P; H4H30089P2; H4H30071P; H4H30066P; H4H30102P2; H4H30076P; H4H30105P2; H4H30108P2; H4H30117P2; H4H30045P; H4H30061P; H4H30095P2; or H4H30093P2). For example, the present invention includes anti-FGFR3 antibodies comprising a mutation in the CH2 region or CH3 region of the Fc domain, wherein the mutation increases the affinity of the Fc domain for FcRn in an acidic environment (e.g., in endosomes where the pH range is about 5.5 to about 6.0). Such mutations can result in an increase in the serum half-life of the antibody when administered to animals.

[0995] Non-limiting examples of such Fc modifications include, for example, modifications at the following positions:

[0996] 250 (e.g., E or Q);

[0997] 250 and 428 (e.g., L or F);

[0998] 252 (e.g., L / Y / F / W or T),

[0999] 254 (e.g., S or T), and / or

[1000] 256 (e.g., S / R / Q / E / D or T);

[1001] and / or modifications at the following positions:

[1002] 428 and / or 433 (e.g., H / L / R / S / P / Q or K), and / or

[1003] 434 (e.g., A, W, H / F, or Y);

[1004] and / or modifications at the following positions:

[1005] 250 and / or 428;

[1006] and / or modifications at the following positions:

[1007] 307 or 308 (e.g., 308F, V308F) and / or

[1008] ·434.

[1009] In one embodiment of the invention, the modification comprises:

[1010] 428L (e.g., M428L) and 434S (e.g., N434S) modifications;

[1011] 428L, 259I (e.g., V259I), and 308F (e.g., V308F) modifications;

[1012] 433K (e.g., H433K) and 434 (e.g., 434Y) modifications;

[1013] 252, 254, and 256 (e.g., 252Y, 254T, and 256E) modifications;

[1014] 250Q and 428L modifications (e.g., T250Q and M428L); and / or

[1015] 307 and / or 308 modifications (e.g., 308F or 308P).

[1016] For example, the invention includes anti-FGFR3 antibodies comprising an Fc domain comprising one or more pairs or one or more groups of mutations selected from the group consisting of:

[1017] 250Q and 248L (e.g., T250Q and M248L);

[1018] 252Y, 254T, and 256E (e.g., M252Y, S254T, and T256E);

[1019] 257I and 311I (e.g., P257I and Q311I);

[1020] 257I and 434H (e.g., P257I and N434H);

[1021] 376V and 434H (for example, D376V and N434H);

[1022] 307A, 380A, and 434A (e.g., T307A, E380A, and N434A);

[1023] 428L and 434S (e.g., M428L and N434S); and

[1024] 433K and 434F (e.g., H433K and N434F).

[1025] In yet another embodiment, the modification comprises a 265A (eg, D265A) and / or a 297A (eg, N297A) modification.

[1026] In one embodiment of the present invention, the heavy chain constant domain is gamma-4 comprising S228P and / or S108P mutations. See Angal et al., A single amino acid substitution abolishes the heterogeneity of chimeric mouse / human (IgG4) antibody, Mol Immunol. 1993 Jan; 30(1): 105-108.

[1027] All possible combinations of the aforementioned Fc domain mutations and other mutations within the antibody variable domains disclosed herein are contemplated within the scope of the present invention.

[1028] The anti-FGFR3 antibodies of the present invention may comprise a modified Fc domain with reduced effector function. As used herein, a "modified Fc domain with reduced effector function" means any Fc portion of an immunoglobulin that has been modified, mutated, truncated, etc. relative to a wild-type naturally occurring Fc domain, such that the molecule comprising the modified Fc exhibits a reduced severity or degree of at least one effect selected from the group consisting of: cell killing (e.g., ADCC and / or CDC), complement activation, phagocytosis, and opsonization relative to a comparison molecule comprising a wild-type naturally occurring Fc portion. In certain embodiments, a "modified Fc domain with reduced effector function" is an Fc domain that has reduced or attenuated binding to an Fc receptor (e.g., FcγR).

[1029] In certain embodiments of the present invention, the modified Fc domain is a variant IgG1 Fc or a variant IgG4 Fc comprising a substitution in the hinge region. For example, the modified Fc used in the context of the present invention may comprise a variant IgG1 Fc, wherein at least one amino acid in the hinge region of the IgG1 Fc is replaced by a corresponding amino acid from the hinge region of the IgG2 Fc. Alternatively, the modified Fc used in the context of the present invention may comprise a variant IgG4 Fc, wherein at least one amino acid in the hinge region of the IgG4 Fc is replaced by a corresponding amino acid from the hinge region of the IgG2 Fc. Non-limiting exemplary modified Fc regions that can be used in the context of the present invention are listed in U.S. Patent Application Publication No. 2014 / 0243504, the disclosure of which is hereby incorporated by reference in its entirety, as well as any functionally equivalent variants of the modified Fc regions listed therein.

[1030] The present disclosure also includes antigen-binding proteins, antibodies or antigen-binding fragments comprising HCVRs listed herein and chimeric heavy chain constant (CH) regions, wherein the chimeric CH region comprises a segment of a CH region derived from more than one immunoglobulin isotype. For example, an antibody of the present disclosure may include a chimeric CH region comprising part or all of a CH2 domain derived from a human IgG1, human IgG2 or human IgG4 molecule, which is combined with a CH3 domain derived from a human IgG1, human IgG2 or human IgG4 molecule. According to certain embodiments, an antibody of the present disclosure includes a chimeric CH region with a chimeric hinge region. For example, a chimeric hinge may include an "upper hinge" amino acid sequence derived from a human IgG1, human IgG2 or human IgG4 hinge region (amino acid residues from positions 216 to 227 according to EU numbering), which is combined with a "lower hinge" sequence derived from a human IgG1, human IgG2 or human IgG4 hinge region (amino acid residues from positions 228 to 236 according to EU numbering). According to certain embodiments, the chimeric hinge region comprises amino acid residues derived from the upper hinge of human IgG1 or human IgG4 and amino acid residues derived from the lower hinge of human IgG2. In certain embodiments, antibodies comprising a chimeric CH region as described herein can exhibit modified Fc effector functions that do not adversely affect the therapeutic or pharmacokinetic properties of the antibody. (See, for example, WO2014 / 022540).

[1031] Other modified Fc domains and Fc modifications that can be used in the context of the present invention include any of the modifications listed in the following documents: US2014 / 0171623; US8697396; US2014 / 0134162; WO2014 / 043361, the disclosures of which are hereby incorporated by reference in their entireties. Methods for constructing antibodies or other antigen-binding fusion proteins comprising modified Fc domains as described herein are known in the art.

[1032] In some cases, the anti-FGFR3 antibody may comprise one or more mutations in the framework region (e.g., in the CH1 domain, CH2 domain, CH3 domain, hinge region, or a combination thereof). In some embodiments, the one or more mutations are used to stabilize the antibody and / or increase half-life. In some embodiments, the one or more mutations are used to modulate Fc receptor interactions to reduce or eliminate Fc effector function, such as FcγR, antibody-dependent cell-mediated cytotoxicity (ADCC), or complement-dependent cytotoxicity (CDC). In additional embodiments, the one or more mutations are used to modulate glycosylation.

[1033] In some embodiments, one, two or more mutations (e.g., amino acid substitutions) are introduced into the Fc region of an antibody described herein (e.g., the CH2 domain (residues 231 to 340 of human IgG1) and / or the CH3 domain (residues 341 to 447 of human IgG1) and / or the hinge region, wherein numbering is according to the Kabat numbering system (e.g., the EU index in Kabat)) to alter one or more functional properties of the antibody, such as serum half-life, complement fixation, Fc receptor binding and / or antigen-dependent cellular cytotoxicity. In some embodiments, one, two or more mutations (e.g., amino acid substitutions) are introduced into the hinge region of the Fc region (CH1 domain) such that the number of cysteine residues in the hinge region is altered (e.g., increased or decreased), as described, e.g., in U.S. Patent No. 5,677,425. The number of cysteine residues in the hinge region of the CH1 domain can be altered, e.g., to facilitate assembly of the light and heavy chains, or to alter (e.g., increase or decrease) the stability of the antibody, or to facilitate linker conjugation.

[1034] In certain embodiments, one, two or more amino acid mutations (i.e., substitutions, insertions or deletions) are introduced into IgG constant domains or their FcRn binding fragments (preferably Fc or hinge-Fc domain fragments) to change (e.g., reduce or increase) the in vivo half-life of the antibody. See, for example, PCT Publication No. WO 02 / 060919; WO 98 / 23289; and WO 97 / 34631; and U.S. Patent Nos. 5,869,046, 6,121,022, 6,277,375 and 6,165,745, as examples of mutations that will change (e.g., reduce or increase) the in vivo half-life of the antibody. In certain embodiments, the Fc region is included in a mutation at residue positions L234, L235 or a combination thereof. In certain embodiments, the mutation includes L234 and L235. In certain embodiments, the mutation includes L234A and L235A.

[1035] Immunoconjugates

[1036] The present invention encompasses anti-FGFR3 (e.g., monomeric or dimeric FGFR3b) antigen binding proteins (e.g., antibodies or antigen binding fragments) conjugated to another moiety (e.g., a therapeutic moiety) ("immunoconjugate") (e.g., H4H30063P; H4H30089P2; H4H30071P; H4H30066P; H4H30102P2; H4H30076P; H4H30105P2; H4H30108P2; H4H30117P2; H4H30045P; H4H30061P; H4H30095P2; or H4H30093P2). In one embodiment of the invention, the anti-FGFR3 antigen binding protein (e.g., antibody or antigen binding fragment) is conjugated to any of the additional therapeutic agents listed herein. As used herein, the term "immunoconjugate" refers to an antigen binding protein (e.g., an antibody or antigen binding fragment) that is chemically or biologically linked to another antigen binding protein, drug, radiopharmaceutical, reporter moiety, enzyme, peptide, protein, or therapeutic agent.

[1037] Treatment and administration

[1038] The present invention provides a method for treating or preventing an FGFR3-mediated disorder in a subject, the method comprising: administering to the subject a therapeutically effective amount of an anti-FGFR3 (e.g., monomeric or dimeric FGFR3b) antigen binding protein (e.g., H4H30063P; H4H30089P2; H4H30071P; H4H30066P; H4H30102P2; H4H30076P; H4H30105P2; H4H30108P2; H4H30117P2; H4H30045P; H4H30061P; H4H30095P2; or H4H30093P2); optionally in combination with an additional therapeutic agent.

[1039] An FGFR3-mediated disorder is any disorder mediated at least in part by FGFR3 activity, e.g., tyrosine kinase activity of FGFR3 or activity of a molecule downstream of FGFR3, e.g., CD73 or the MEK pathway in tumor cells expressing FGFR3.

[1040] FGFR3-mediated disorders can also include T cell suppression mediated by tumor cells expressing FGFR3, for example, adenosine-mediated T cell suppression via the A2A receptor, for example, where CD73 catalyzes the conversion of AMP to adenosine. CD73 (NT5E, ecto-5'-nucleotidase) is a glycosylphosphatidylinositol-(GPI-) anchored cell surface enzyme that plays a key role in purinergic signaling pathways by dephosphorylating AMP (adenosine monophosphate) to adenosine. Extracellular adenosine itself is involved in tumor immune evasion and tumor cell invasion, while the non-enzymatic functions of CD73 are related to cell adhesion and migration of tumor cells.

[1041] FGFR3-mediated disorders include, for example:

[1042] ·cancer,

[1043] Bladder cancer,

[1044] Brain cancer,

[1045] Breast cancer,

[1046] Cervical cancer,

[1047] Colorectal cancer,

[1048] Endometrial cancer,

[1049] Gastric cancer,

[1050] Head and neck cancer,

[1051] Kidney cancer,

[1052] Lung cancer,

[1053] Multiple myeloma,

[1054] Ovarian cancer,

[1055] Pancreatic cancer,

[1056] Urothelial carcinoma,

[1057] Achondroplasia,

[1058] Cruzon syndrome with acanthosis nigricans,

[1059] Epidermal nevus,

[1060] Decreased cartilage production,

[1061] LADD syndrome,

[1062] Muenke syndrome,

[1063] severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), and / or

[1064] ·Thalassemic dysplasia.

[1065] Achondroplasia is a form of short-limbed dwarfism. Cruzon syndrome with acanthosis nigricans is a condition that causes the skull bones to join together prematurely (craniosynostosis), resulting in a malformed head and distinctive facial features, as well as a skin abnormality called acanthosis nigricans, characterized by the presence of thick, dark, velvety skin in the folds and wrinkles of the body. Epidermal nevi are abnormal skin growths composed of skin cells called keratinocytes. Hypochondrogenesis is a form of short-limbed dwarfism with milder symptoms than achondroplasia. Lacrimal-auricular-dental-digital (LADD) syndrome is an extremely rare genetic disorder characterized by abnormalities affecting the tear and salivary glands and ducts, ears, teeth, and fingers and toes. The most common symptoms include malformations of the network of structures that secrete and drain tears from the eyes (the lacrimal apparatus), as well as abnormalities of the forearms and fingers. Specific symptoms can vary greatly from person to person. LADD syndrome can occur sporadically or be inherited in an autosomal dominant pattern. Muenke syndrome is a condition that causes craniosynostosis, resulting in a malformed head and distinctive facial features. Additional signs and symptoms may include hearing loss, mild abnormalities of the hands and feet, and developmental delay. SADDAN (severe achondroplasia with developmental delay and acanthosis nigricans) is characterized by short-limb dwarfism (achondroplasia); severe developmental delay; and thick, dark, velvety skin. Thalassifying dysplasia is a severe skeletal disorder characterized by extremely short limbs and the presence of superfluous (redundant) wrinkles on the arms and legs. Other features of the condition include a narrow chest, short ribs, underdeveloped lungs, and an enlarged head with a large forehead and protruding eyes with wide-set eyes. Bladder cancer includes non-muscle invasive bladder cancer (NMIBC) and muscle invasive bladder cancer (MIBC).

[1066] An effective or therapeutically effective amount of an anti-FGFR3 antigen binding protein (e.g., an antibody or antigen binding fragment) for treating or preventing an FGFR3-mediated disorder refers to an amount of the antigen binding protein that is sufficient to alleviate one or more signs and / or symptoms of the disease or disorder of the subject being treated, whether by inducing the regression or elimination of such signs and / or symptoms, or by inhibiting the progression of such signs and / or symptoms. In one embodiment of the invention, the effective or therapeutically effective amount of an anti-FGFR3 antigen binding protein is about 2 mg / kg to 30 mg / kg. The dosage can be administered, for example, approximately once a month. The dosage can vary depending on the age and size of the subject to be administered, the target disease, the disorder, the route of administration, etc. In certain embodiments, a second or multiple subsequent doses of the antigen binding protein may be administered after the initial dose, the amount of which may be roughly the same or less or more than the initial dose, with the subsequent doses spaced several days, weeks, or months apart.

[1067] The present invention provides a method for administering an anti-FGFR3 (e.g., monomeric or dimeric FGFR3b) antigen binding protein (e.g., an antibody or antigen-binding fragment thereof (e.g., H4H30063P; H4H30089P2; H4H30071P; H4H30066P; H4H30102P2; H4H30076P; H4H30105P2; H4H30108P2; H4H30117P2; H4H30045P; H4H30061P; H4H30095P2; or H4H30093P2)) to a subject, the method comprising: introducing the protein or a pharmaceutical formulation thereof into the subject. For example, in one embodiment of the invention, the method comprises: piercing the subject's body, for example with a needle of a syringe, and injecting the antigen binding protein or a pharmaceutical formulation thereof into the subject's body, for example, into the subject's eye, vein, artery, muscle tissue, or subcutaneous tissue.

[1068] As used herein, the term "subject" refers to a mammal (e.g., rat, mouse, cat, dog, cattle, sheep, horse, goat, rabbit), preferably a human, for example, in need of prevention and / or treatment of an FGFR3-mediated disorder. The subject may suffer from an FGFR3-mediated disorder or be susceptible to developing such a disorder. In one embodiment of the invention, the subject has an FGFR3 genotype selected from the following: S249C, R248C, G372C, Y375C, K650E, and / or FGFR3-TACC3 (e.g., heterozygous or homozygous).

[1069] Combinations and pharmaceutical formulations

[1070] The present invention provides compositions comprising an anti-FGFR3 (e.g., monomeric or dimeric FGFR3b) antigen binding protein, such as an antibody or antigen binding fragment (e.g., H4H30063P; H4H30089P2; H4H30071P; H4H30066P; H4H30102P2; H4H30076P; H4H30105P2; H4H30108P2; H4H30117P2; H4H30045P; H4H30061P; H4H30095P2; or H4H30093P2), in combination with one or more components; and methods of use thereof and methods of preparing such compositions. Pharmaceutical formulations comprising an anti-FGFR3 antigen binding protein and a pharmaceutically acceptable carrier or excipient are part of the invention.

[1071] To prepare a pharmaceutical formulation of an anti-FGFR3 antigen binding protein (e.g., an antibody and antigen-binding fragments thereof (e.g., H4H30063P; H4H30089P2; H4H30071P; H4H30066P; H4H30102P2; H4H30076P; H4H30105P2; H4H30108P2; H4H30117P2; H4H30045P; H4H30061P; H4H30095P2; or H4H30093P2)), the antigen binding protein is mixed with a pharmaceutically acceptable carrier or excipient. See, e.g., Remington's Pharmaceutical Sciences and US Pharmacopeia: National Formulary, Mack Publishing Company, Easton, Pa. (1984); Hardman et al. (2001) Goodman and Gilman's The Pharmacological Basis of Therapeutics, McGraw-Hill, New York, NY; Gennaro (2000) Remington: The Science and Practice of Pharmacy, Lippincott, Williams, and Wilkins, New York, NY; Avis et al. (eds.) (1993) Pharmaceutical Dosage Forms: Parenteral Medications, Marcel Dekker, NY; Lieberman et al. (eds.) (1990) Pharmaceutical Dosage Forms: Tablets, Marcel Dekker, NY; Lieberman et al. (eds.) (1990) Pharmaceutical Dosage Forms: Disperse Systems, Marcel Dekker, NY; Weiner and Kotkoskie (2000) Excipient Toxicity and Safety, Marcel Dekker, Inc., New York, NY. In one embodiment of the present invention, the pharmaceutical formulation is sterile. Such compositions are part of the present invention.

[1072] The pharmaceutical formulations of the present invention comprise an anti-FGFR3 antigen binding protein (e.g., H4H30063P; H4H30089P2; H4H30071P; H4H30066P; H4H30102P2; H4H30076P; H4H30105P2; H4H30108P2; H4H30117P2; H4H30045P; H4H30061P; H4H30095P2; or H4H30093P2) and a pharmaceutically acceptable carrier, including, for example, water and a buffer.

[1073] The scope of the present invention includes: a dried (e.g., freeze-dried) composition comprising an anti-FGFR3 antigen binding protein (e.g., an antibody or antigen-binding fragment thereof (e.g., H4H30063P; H4H30089P2; H4H30071P; H4H30066P; H4H30102P2; H4H30076P; H4H30105P2; H4H30108P2; H4H30117P2; H4H30045P; H4H30061P; H4H30095P2; or H4H30093P2)); or a pharmaceutical formulation thereof, which comprises a pharmaceutically acceptable carrier but is substantially free of water.

[1074] In another embodiment of the invention, the additional therapeutic agent disclosed herein that is administered to a subject in combination with an anti-FGFR3 antigen binding protein, e.g., an antibody or antigen-binding fragment thereof (e.g., H4H30063P; H4H30089P2; H4H30071P; H4H30066P; H4H30102P2; H4H30076P; H4H30105P2; H4H30108P2; H4H30117P2; H4H30045P; H4H30061P; H4H30095P2; or H4H30093P2) is administered to the subject according to the Physicians' Desk Reference 2003 (Thomson Healthcare; 57th Edition (November 1, 2002)).

[1075] The mode of administration of the anti-FGFR3 antigen binding protein or its composition can be varied. The routes of administration include parenteral, non-parenteral, oral, rectal, transmucosal, intestinal, parenteral; intramuscular, subcutaneous, intradermal, intramedullary, intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, intraocular, inhalation, insufflation, topical, cutaneous, intraocular, intravitreal, transdermal or intraarterial.

[1076] The present invention provides a container (e.g., a plastic or glass vial (e.g., with a cap or chromatography column), a hollow bore needle, or a syringe barrel) comprising any one of an anti-FGFR3 antigen binding protein (e.g., an antibody or antigen-binding fragment thereof (e.g., H4H30063P; H4H30089P2; H4H30071P; H4H30066P; H4H30102P2; H4H30076P; H4H30105P2; H4H30108P2; H4H30117P2; H4H30045P; H4H30061P; H4H30095P2; or H4H30093P2)), or a pharmaceutical formulation comprising a pharmaceutically acceptable carrier thereof.

[1077] The present invention includes compositions comprising an anti-FGFR3 antigen binding protein (e.g., an antibody of the invention or an antigen-binding fragment thereof (e.g., H4H30063P; H4H30089P2; H4H30071P; H4H30066P; H4H30102P2; H4H30076P; H4H30105P2; H4H30108P2; H4H30117P2; H4H30045P; H4H30061P; H4H30095P2; or H4H30093P2)) in combination with one or more additional therapeutic agents. The anti-FGFR3 antigen binding protein and the additional therapeutic agent can be in a single composition or in separate compositions. For example, in one embodiment of the invention, the additional therapeutic agent is a cancer therapeutic agent. In one embodiment of the invention, the additional therapeutic agent is

[1078] FGFR inhibitors (eg, erdafitinib)

[1079] Pemitinib,

[1080] Infigratinib,

[1081] Rogatinib,

[1082] Dexamethasone

[1083] Alkylating drugs (e.g., altretinoin, trabectedin, or busulfan),

[1084] Nitrosoureas (for example, carmustine or lomustine),

[1085] Cytotoxic antibiotics (e.g., anthracyclines, doxorubicin, valrubicin, bleomycin, or dactinomycin),

[1086] antimetabolites (e.g., methotrexate, floxuridine, clofarabine, or pralatrexate),

[1087] Vinca alkaloids (for example, vinblastine, vinorelbine, vincristine, or vindesine),

[1088] Photodynamic drugs (eg, porfimer sodium or aminolevulinic acid),

[1089] Platinum drugs (cisplatin or phenanthriplatin),

[1090] Taxanes (e.g., paclitaxel or docetaxel),

[1091] Topoisomerase inhibitors (for example, irinotecan, topotecan, etoposide, or teniposide),

[1092] ·ziv-aflibercept

[1093] Anti-cancer antibodies (for example, rituximab, trastuzumab, cetuximab, cemiplimab, pembrolizumab, panitumumab, or bevacizumab).

[1094] As discussed herein, the present invention includes methods for treating or preventing FGFR3-mediated disorders in a subject in need of such treatment or prevention by administering an anti-FGFR3 antigen binding protein (e.g., H4H30063P; H4H30089P2; H4H30071P; H4H30066P; H4H30102P2; H4H30076P; H4H30105P2; H4H30108P2; H4H30117P2; H4H30045P; H4H30061P; H4H30095P2; or H4H30093P2), which can be associated with an additional therapeutic agent.

[1095] The term "in combination with " indicates that the components of the present invention, anti-FGFR3 antigen binding proteins (e.g., antibodies or antigen binding fragments thereof) and another agent (such as methotrexate) can be formulated into a single composition, for example, for simultaneous delivery, or formulated into two or more compositions (e.g., a kit comprising each component). The components administered in combination with each other can be administered to the subject at a different time than when the other component is administered; for example, each administration can be performed non-simultaneously (e.g., independently or sequentially) at intervals within a given time period. The independent components administered in combination with each other can also be administered sequentially (although substantially simultaneously) during the same administration period. In addition, the independent components administered in combination with each other can be administered to the subject by the same or different routes.

[1096] Examples

[1097] Example 1 : Binding kinetics

[1098] The Biacore binding kinetics of anti-FGFR3 antibodies in antibody-capture format to monomeric human FGFR3b, cynomolgus monkey FGFR3b, murine FGFR3b, human FGFR3c, and dimeric human FGFR3b extracellular domain recombinant proteins were analyzed at 25°C.

[1099] Using Biacore 3000 or Biacore The 4000 instrument used real-time surface plasmon resonance biosensor technology to determine the equilibrium dissociation constant (K) for binding of human FGFR3b expressed with a C-terminal myc-myc-hexahistidine tag (hFGFR3b.mmH, REGN3152), cynomolgus monkey FGFR3b expressed with a C-terminal myc-myc-hexahistidine tag (mfFGFR3b.mmH, REGN3521), mouse FGFR3b expressed with a C-terminal myc-myc-hexahistidine tag (mFGFR3b.mmH, REGN3215), human FGFR3c expressed with a C-terminal myc-myc-hexahistidine tag (hFGFR3c.mmH, REGN3155), or human FGFR3b expressed with a C-terminal mouse Fc tag (hFGFR3b.mFc, REGN3153) to purified anti-FGFR3 antibodies. D Values. The CM5 Biacore sensor surface was derivatized by amine coupling with a monoclonal mouse anti-human Fc monoclonal antibody (REGN2567). All Biacore binding studies were performed in a buffer consisting of 0.01 M HEPES pH 7.4, 0.15 M NaCl, 3 mM EDTA, and 0.05% v / v surfactant P20 (HBS-EP running buffer). Different concentrations of monomeric protein (ranging from 90 nM to 3.33 nM, 3-fold serial dilutions) prepared in HBS-EP running buffer or dimeric protein (hFGFR3b.mFc, REGN3153) (ranging from 30 nM to 10 nM, 3-fold serial dilutions) prepared in HBS-EP running buffer were injected over the captured anti-FGFR3 antibody at a flow rate of 30 μL / min. Antibody-reagent association was monitored for 5 minutes, while dissociation was monitored for 10 minutes in HBS-EP running buffer. At the end of each cycle, a 10 s injection of 20 mM phosphoric acid was used to regenerate the anti-FGFR3 antibody capture surface. All binding kinetics experiments were performed at 25°C.

[1100] Specific SPR-Biacore sensorgrams were obtained by a double referencing procedure. Double referencing was performed by first subtracting the signal of each injection on the reference surface (anti-hFc) from the signal on the experimental surface (anti-hFc captured anti-FGFR3 antibody) to remove the effect of refractive index changes. In addition, running buffer injection was performed to allow subtraction of signal changes caused by dissociation of the captured antibody from the coupled anti-hFc surface. The kinetic association (k) was determined by fitting the real-time sensorgrams to a 1:1 binding model using Scrubber v2.0c curve fitting software. a ) and dissociation (k d ) rate constant. The binding and dissociation equilibrium constant (K) was calculated based on the kinetic rate constant. D ) and dissociation half-life (t1 / 2) are:

[1101] and

[1102] The monomer kinetic results are presented in Tables 1-1 to 1-4. The dimer kinetic results are presented in Table 1-5.

[1103] REGN3152 (expressed as human FGFR3b with a C-terminal myc-myc-hexahistidine tag (hFGFR3b.mmH)) ESLGTEQRVVGRAAEVPGPEPGQQEQLVFGSGDAVELSCPPPGGGPMGPTVWVKDGTGLVPSERVLVGPQRLQVLNASHEDSGAYSCRQRLTQRVLCHFSVRVTDAPSSGDDEDGEDEAEDTGVDTGAPYWTRPERMDKKLLAVPAANTVRFRCPAAGNPTPSISWLKNGREFRGEHRIGGIKLRHQQWSLVM ESVVPSDRGNYTCVVENKFGSIRQTYTLDVLERSPHRPILQAGLPANQTAVLGSDVEFHCKVYSDAQPHIQWLKHVEVNGSKVGPDGTPYVTVLKSWISESVEADVRLRLANVSERDGGEYLCRATNFIGVAEKAFWLSVHGPRAAEEELVEADEAGSVYAGEQKLISEEDLGGEQKLISEEDLHHHHHH(SEQ ID NO:238)

[1104] REGN3153 (expressed as human FGFR3b with a C-terminal murine Fc tag (hFGFR3b.mFc))

[1105] ESLGTEQRVVGRAAEVPGPEPGQQEQLVFGSGDAVELSCPPPGGGPMGPTVWVKDGTGLVPSERVLVGPQRLQVLNASHEDSGAYSCRQRLTQRVLCHFSVRVTDAPSSGDDEDGEDEAEDTGVDTGAPYWTRPERMDKKLLAVPAANTVRFRCPAAGNPTPSISWLKNGREFRGEHRIGGIKLRHQQWSLVMESVVPSDRGNYTCVVENKFGSIRQTYTLDVLERSPHRPILQAGLPANQTAVLGSDVEFHCKVYSDAQPHIQWLKHVEVNGSKVGPDGTPYVTVLKSWISESVEADVRLRLANVSERDGGEYLCRATNFIGVAEKAFWLSVHGPRAAEEELVEADEAGSVYAGEPRGPTIKPCPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGK(SEQ ID NO:239)

[1106] REGN3215 (expressing murine FGFR3b with a C-terminal myc-myc-hexahistidine tag (mFGFR3b.mmH))

[1107] EPPGPEQRVVRRAAEVPGPEPSQQEQVAFGSGDTVELSCHPPGGAPTGPTVWAKDGTGLVASHRILVGPQRLQVLNASHEDAGVYSCQHRLTRRVLCHFSVRVTDAPSSGDDEDGEDVAEDTGAPYWTRPERMDKKLLAVPAANTVRFRCPAAGNPTPSISWLKNGKEFRGEHRIGGIKLRHQQWSLVMESVVPSDRGNYTCVVENKFGSIRQTYTLDVLERSPHRPILQAGLPANQTAILGSDVEFHCKVYSDAQPHIQWLKHVEVNGSKVGPDGTPYVTVLKSWISENVEADARLRLANVSERDGGEYLCRATNFIGVAEKAFWLRVHGPQAAEEELMETDEAGSVYAGEQKLISEEDLGGEQKLISEEDLHHHHHH(SEQ ID NO:240)

[1108] REGN3155 (expressed as human FGFR3c with a C-terminal myc-myc-hexahistidine tag (hFGFR3c.mmH))

[1109] ESLGTEQRVVGRAAEVPGPEPGQQEQLVFGSGDAVELSCPPPGGGPMGPTVWVKDGTGLVPSERVLVGPQRLQVLNASHEDSGAYSCRQRLTQRVLCHFSVRVTDAPSSGDDEDGEDEAEDTGVDTGAPYWTRPERMDKKLLAVPAANTVRFRCPAAGNPTPSISWLKNGREFRGEHRIGGIKLRHQQWSLVMESVVPSDRGNYTCVVENKFGSIRQTYTLDVLERSPHRPILQAGLPANQTAVLGSDVEFHCKVYSDAQPHIQWLKHVEVNGSKVGPDGTPYVTVLKTAGANTTDKELEVLSLHNVTFEDAGEYTCLAGNSIGFSHHSAWLVVLPAEEELVEADEAGSVYAGEQKLISEEDLGGEQKLISEEDLHHHHHH(SEQ ID NO:241)

[1110] REGN3521(mf FGFR3b extracellular (R357G)(E23-G377; R357G).mmH)

[1111] ESLGTEQRVVGRVAEVSGPEPSQQEQLVFGSGDAVELSCPPPGGGPMGPTVWVKDGAGLVPSERVLVGPQRLQVLNASHEDSGAYSCRQRLTQLVLCHFSVRVTDAPSSGDDEDGEDEAEDTGVDTGAPYWTRPERMDKKLLAVPAANTVRFRCPAAGNPTPSISWLKNGKEFRGEHRIGGIKLRHQQWSLVM ESVVPSDRGNYTCVVENKFGSIRQTYTLDVLERSPHRPILQAGLPANQTAVLGSDVEFHCKVYSDAQPHIQWLKHVEVNGSKVGPDGTPYVTVLKSWISESVEADVRLRLANVSERDGGEYLCRATNFIGVAEKAFWLSVHGPRAAEEELVEADEAGSVYAGEQKLISEEDLGGEQKLISEEDLHHHHHH(SEQ ID NO:242)

[1112] Table 1-1. Kinetic and equilibrium binding parameters of monomeric human FGFR3b to surface-captured anti-FGFR3 antibodies at 25°C

[1113]

[1114] *See V listed in WO2016 / 134234 H and V L

[1115] REGN6331 heavy chain

[1116] EVQLVESGGGLVQPGGSLRLSCAASGFTFTSTGISWVRQAPGKGLEWVGRIYPTSGSTNYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARTYGIYDLYVDYTEYVMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:243)

[1117] REGN6331 light chain

[1118] DIQMTQSPSSLSASVGDRVTITCRASQDVDTSLAWYKQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSTGHPQTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ IDNO:244)

[1119] Table 1-2. Kinetic and equilibrium binding parameters of monomeric cynomolgus monkey FGFR3b with surface-tethered anti-FGFR3 antibodies at 25 °C

[1120]

[1121] *NB = Non-binding

[1122] **NT = Not tested

[1123] Table 1-3. Kinetic and equilibrium binding parameters of monomeric murine FGFR3b to surface-captured anti-FGFR3 antibodies at 25°C

[1124]

[1125]

[1126] *NA: Not acquired. Data acquisition and analysis were hampered due to technical issues.

[1127] **NB = Non-Bound

[1128] ***NT: Not tested

[1129] Table 1-4. Kinetic and equilibrium binding parameters of monomeric human FGFR3c to surface-captured anti-FGFR3 antibodies at 25°C

[1130]

[1131] *NB = Non-Bound

[1132] Table 1-5. Kinetic and equilibrium binding parameters of dimeric human FGFR3b to surface-captured anti-FGFR3 antibodies at 25°C

[1133]

[1134]

[1135] *NA = Not available. Data acquisition and analysis were hampered by technical issues.

[1136] **NT = Not Tested

[1137] Example 2 : Blocking assay

[1138] Anti-FGFR3 antibodies that blocked the binding of dimeric human FGFR3b or FGFR3c to human FGF acidic or FGF basic were analyzed by ELISA.

[1139] Table 2-1. Reagents used

[1140]

[1141]

[1142] An ELISA-based blocking assay was developed to determine the ability of anti-FGFR3 antibodies to block the binding of human fibroblast growth factor receptor 3 isoform b (hFGFR3b) or human fibroblast growth factor receptor 3 isoform c (hFGFR3c) to either the acidic (hFGFacidic) or basic (hFGFbasic) ligands of human fibroblast growth factor.

[1143] The people FGFR3b recombinant protein used in the experiment has the hFGFR3b extracellular domain (amino acid E23-G377) (hFGFR3b-mFc, accession number NM_001163213.1) that is expressed as the Fc part with mouse IgG2a at C-terminal (amino acid E98-K330) place.HFGFR3c and hFGF acidic protein are commercially available.People FGFR3c albumen has the hFGFR3c extracellular domain (amino acid Glu23-Gly375) (hFGFR3c-hFc, accession number P22607) that is expressed as the Fc part with human IgG1 at C-terminal (amino acid Pro100-Lys330) place, and hFGF acidic protein is expressed as and has amino acid Ala2-Asp155 (accession number P05230.1).HFGF basic protein is commercially available. It is expressed with amino acids Ala144-Ser288 (accession number NM_002006).

[1144] In the blocking assay, 96-well microtiter plates were coated with 2 mg / ml of hFGF acidic or hFGF basic in PBS + 10 mg / ml heparin overnight at 4°C. Nonspecific binding sites were subsequently blocked using 0.5% (w / v) BSA + 10 μg / ml heparin in PBS. In other 96-well microtiter plates, a fixed amount of 4 nM hFGFR3b-mFc, 0.4 nM, or 7 nM hFGFR3c-hFc was combined with anti-FGFR3, anti-FGFR3 comparator, or irrelevant human IgG1 or IgG4 isotype antibodies for one hour at dilutions ranging from 3.4 pM to 200 nM in PBS + 0.5% BSA + 10 μg / ml heparin. The fixed concentration of hFGFR3b or hFGFR3c protein was selected to produce approximately 50% maximal binding (EC) of hFGFR3b or hFGFR3c protein to the plate. 50The concentration of hFGFR3b-mFc or hFGFR3c-hFc was determined by ELISA. The antibody complex with 4 nM hFGFR3b-mFc or 0.4 nM hFGFR3c-hFc was transferred to a microtiter plate coated with hFGF acidic protein. Simultaneously, the antibody complex with 7 nM hFGFR3c-hFc was added to a microtiter plate coated with hFGF basic protein. After incubation for 1 hour at room temperature, the plates were washed and plate-bound hFGFR3b-mFc or hFGFR3c-hFc protein was detected using horseradish peroxidase (HRP)-conjugated goat anti-mouse or goat anti-human Fcγ fragment-specific antibodies. The plates were then developed using TMB substrate solution (BD Biosciences) according to the manufacturer's recommended protocol, and the absorbance at 450 nm was measured on a Victor X5 microplate reader.

[1145] Binding data were analyzed using a sigmoidal (four-parameter logistic) dose-response model using GraphPad Prism software. IC 50 The value (defined as the antibody concentration required to block 50% of hFGFR3b-mFc or hFGFR3c-hFc binding to plate-coated hFGF acidic or hFGF basic protein) was used as an indicator of blocking efficacy. The blocking percentage of FGFR3 antibodies at a given concentration was calculated based on the formula shown below.

[1146]

[1147] Antibodies that blocked binding by greater than 50% at the highest tested concentration were classified as blockers and the IC 50 value.

[1148] A sandwich ELISA-based blocking assay was used to evaluate the ability of anti-FGFR3 antibodies to block the binding of human FGFR3b to hFGF acidic protein, or hFGFR3c to hFGF acidic or hFGF basic protein. In this assay, a fixed concentration of hFGFR3b-mFc or hFGFR3c-hFc was preincubated with a wide range of anti-FGFR3 antibody concentrations before binding to plate-immobilized hFGF acidic or basic protein. Plate-bound hFGFR3b-mFc or hFGFR3c-hFc was detected using HRP-conjugated goat anti-mouse or goat anti-human Fcγ fragment-specific antibodies, respectively. Six anti-FGFR3 antibodies were evaluated for their inhibition of hFGFR3b-mFc binding to hFGF acidic protein. Antibody H4H30093P2 (which also binds to hFGFR3c) was also tested for inhibition of hFGFR3c-hFc binding to hFGF acidic or hFGF basic proteins. The IC values of the FGFR3 antibodies at the highest tested concentrations are summarized in Table 2-2. 50 value and maximum blocking.

[1149] All six anti-FGFR3 antibodies (H4H30063P, H4H30066P, H4H30071P, H4H30089P2, H4H30093P2, and H4H30102P2) showed concentration-dependent blocking of hFGFR3b-mFc binding to hFGF acidic protein, with the extent of blocking ranging from 68% to 95% at the highest antibody concentration tested (200 nM). The IC values for these blocking antibodies were 0. 50 The values ranged from 2 nM to 15 nM. Antibody H4H30093P2 showed less than 50% blocking of hFGFR3c binding to hFGF acidic or hFGF basic at the highest antibody concentration tested and was classified as a non-blocker for hFGFR3c. The anti-FGFR3 comparator antibody had an IC of 1.5 nM. 50 Blocked the binding of hFGFR3b to hFGF acid with IC values of 0.1 nM and 8.9 nM, respectively. 50 Blocked the binding of hFGFR3c to hFGF acidic or hFGF basic. Human IgG1 or IgG4 isotype control antibodies showed no blocking effect in any assay.

[1150] Table 2-2. IC values of FGFR3 antibodies at the highest tested concentration 50 Value and maximum blocking

[1151]

[1152]

[1153] Nbl: non-blocking, blocking % less than or equal to 50

[1154] ND: Not Determined

[1155] (*) Blockade of hFGFR3b binding to hFGF acidic protein or hFGFR3c binding to hFGF basic protein by anti-FGFR3-hIgG1 comparator and hIgG1 isotype control was tested in independent experiments

[1156] Example 3 :Octet cross-competition analysis of anti-FGFR3 antibodies

[1157] Binding competition between anti-FGFR3 monoclonal antibodies that have previously been identified as binding to hFGFR3b.mmH was determined using real-time label-free biolayer interferometry (BLI) assays on Octet HTX biosensors (ForteBio Corp., ADvision of Pall Life Sciences). The entire experiment was performed at 25° C. in a buffer consisting of 0.01 M HEPES pH 7.4, 0.15 M NaCl, 3 mM EDTA, 0.05% v / v surfactant P20, 0.1 mg / mL BSA (Octet HBS-EP buffer) with the plate shaken at 1000 rpm. In order to assess whether two antibodies can compete with each other and be expressed as hFGFR3b extracellular domain (hFGFR3b.mmH, REGN3152) with C-terminal myc-myc-histidine tag, first by being immersed in the hole containing 20 μ g / mL hFGFR3b.mmH solution through the Octet biosensor (Fortebio Inc, #18-5079) coated with anti-penta His antibody for 23 seconds to capture about 0.2nm of hFGFR3b.mmH on the biosensor.Then with the first anti-FGFR3 monoclonal antibody (hereinafter referred to as mAb-1), the biosensor of capture antigen is soaked by being immersed in the hole containing 50 μ g / mL mAb-1 solution for 5 minutes.Then, subsequently, biosensor is immersed in the hole containing 50 μ g / mL second anti-FGFR3 monoclonal antibody (hereinafter referred to as mAb-2) solution for 3 minutes.Real-time binding response is monitored during the experimental process, and the binding response at the end of each step is recorded. The responses of mAb-2 to hFGFR3b.mmH pre-complexed with mAb-1 were compared, and a 50% inhibition threshold was used to determine the competitive or non-competitive nature of an anti-FGFR3 monoclonal antibody against another antibody. Table 3-1 summarizes cross-competing antibodies that compete for binding to hFGFR3b.mmH regardless of the order of sequential binding of mAb-1 and mAb-2.

[1158] Table 3-1. Cross-competition of anti-FGFR3 antibodies for binding to hFGFR3b.mmH.

[1159]

[1160]

[1161] Example 4 : Characterization of FGFR3 antibodies in cell growth assays using engineered BaF3 cells overexpressing human FGFR3 WT or FGFR3-S249C mutant receptors.

[1162] The ability of anti-FGFR3 antibodies to block FGFR3 signaling was evaluated using a proliferation assay using an engineered IL-3-dependent Ba / F3 murine hematopoietic cell line genetically modified to stably express human fibroblast growth factor receptor 3b wild type or mutant S249C.

[1163] The FGFR3 antigen-binding molecules and controls tested in this experiment are shown in Table 4-1.

[1164] Table 4-1. FGFR3b binding molecules and controls

[1165]

[1166] Cell lines:

[1167] BAF3 / FGFR3b (ACL11991): An IL-3-dependent murine pre-B cell line engineered to stably express full-length human FGFR3b (accession number NP_001156685.1, amino acid sequence M1-T808). Cells were maintained in RPMI 1640 + 10% FBS + P / S / G + 1 ng / ml mouse IL-3 + 500 ug / ml neomycin at 37°C with 5% CO2.

[1168] BAF3 / FGFR3b_S249C (ACL11986): An IL-3-dependent murine pre-B cell line engineered to stably express full-length human FGFR3b (Accession No. NP_001156685.1, amino acid sequence M1-T808, S249C). Cells were maintained in RPMI 1640 + 10% FBS + P / S / G + 1 ng / ml mouse IL-3 + 500 ug / ml neomycin at 37°C in 5% CO2.

[1169] FGFR3 receptors are members of the receptor tyrosine kinase (RTK) family for regulating cell proliferation, survival, differentiation and migration of multicellular organisms. The activation of wild-type (WT) receptors occurs via the combination of its soluble ligand (for example, FGF1), which drives homodimerization and autophosphorylation of FGFR3, thereby ultimately causing activation (Xie et al., FGF / FGFRsignaling in health and disease, Signal Transduction and Targeted Therapy (2020) 5: 181) of too many intracellular signal transduction cascades (such as Ras / MAPK, PLCγ1 / PKC, PI3- kinases / Akt and STAT paths). The FGFR3 mutation causing abnormal FGFR3 activation has been associated with various types of human malignancies. Mutation S249C causes constitutive ligand-independent FGFR3 activation (Tomlinson et al., Knockdown by shRNA identifies S249C mutant FGFR3 as a potential therapeutic target in bladder cancer, Oncogene. 2007 Aug 30;26(40):5889–5899).

[1170] To investigate the blocking effect of anti-FGFR3b antibodies on signal transduction, proliferation assays were performed using engineered IL-3-dependent Ba / F3 murine hematopoietic cell lines genetically modified to stably express human fibroblast growth factor receptor 3b wild type or mutant S249C (FGFR3b-Accession No. NP_001156685.1, amino acids M1-T808) (Kong et al., Ba / F3 transformation assays, Oncotarget, 2017, Vol. 8, No. 22, pp. 35488-35489). In the presence of titrated antibodies, engineered BaF3 / FGFR3b cells were stimulated with ligand (human FGF1) and cell growth was assessed using CellTiter-Glo, which measures ATP (a product of viable proliferating cells).

[1171] Engineered BaF3 / hFGFR (WT or S249C) cells grown in culture medium (RPMI1640+10% FBS+penicillin / streptomycin / L-glutamine+1 ng / mL mouse IL-3+500 ug / mL neomycin) were washed and seeded in IL-3-free culture medium containing 5 ug / ml heparin and 1 nM human FGF1. 5Cells / well were seeded into 96-well white tissue culture plates, and then antibodies were added in a 1:4 serial dilution range from 1.5 pM to 100 nM, including a control without antibody (plotted at 0.4 pM). After the addition of antibodies, the 96-well white microtiter plates were incubated at 37 ° C / 5% CO2 for 72 hours, after which an equal volume of CellTiter-Glo was added. TM (Promega) reagent was used to lyse cells and detect luciferase activity. Emitted light was captured as relative light units (RLU) on a multi-label plate reader Envision (PerkinElmer). The EC of the antibody was determined based on the 4-parameter logistic equation on a 10-point dose-response curve (the 10th point did not contain antibody) using GraphPad Prism software. 50 value.

[1172] Anti-FGFR3b antibodies H4H30063P and H4H30102P2 were tested with comparator antibody REGN6331 and an isotype-matched negative control in the presence of 1 nM FGF1 and 5 ug / ml heparin (see Tables 4-2 and Figure 1 ).

[1173] The anti-FGFR3b antibodies H4H30063P and H4H30102P2 and their corresponding matched isotype control REGN1945 were tested against the comparator antibody REGN6331 and the isotype-matched control REGN1932 in the presence of 1 nM FGF1 + 5 ug / ml heparin. It was observed that in experiments using the BaF3 / hFGFR3b WT cell line, antibodies H4H30063P and REGN6331 exhibited similar maximal levels of proliferation inhibition, while antibody H4H30102P2 did not reach the same maximal level of inhibition. Due to the constitutive FGFR3b activity caused by the S249C mutation, the extent of ligand-mediated growth in BaF3 / FGFR3_S249C cells was minimal. Nevertheless, addition of ligand caused a slight increase in proliferation, which was inhibited to similar maximal levels by antibodies H4H30063P and REGN6331, while H4H30102P2 caused IC 50 A very small suppression where the value cannot be calculated.

[1174] Table 4-2: Maximum inhibition rate and efficacy of antibodies

[1175]

[1176] aMaximum blockade was defined as the mean maximum blockade detected over the dose range tested.

[1177] Abbreviations: ND: not determined; NC: not calculated; potency values could not be determined by PRISM

[1178]

[1179] Examples 5: Characterization of the mechanism of action of FGFR3 antibodies

[1180] Assays were performed to evaluate: (1) inhibition of FGFR3 S249C dimerization using the bladder cancer cell line UMUC14, which carries the endogenous FGFR3 S249C mutation; and (2) inhibition of FGF1 / heparin-induced downstream signaling in BaF3 cells expressing wild-type FGFR3.

[1181] Cell lines:

[1182] UMUC14 (Sigma-Aldrich): cells were maintained in MEM + 1% non-essential amino acids (NEAA) 10% FBS + P / S; 37°C 5% CO2.

[1183] BAF3 / FGFR3b (ACL11991): An IL-3-dependent murine pre-B cell line engineered to stably express full-length human FGFR3b (accession number NP_001156685.1, amino acid sequence M1-T808). Cells were maintained in RPMI 1640 + 10% FBS + P / S / G + 1 ng / ml mouse IL-3 + 500 ug / ml neomycin at 37°C with 5% CO2.

[1184] Reagents:

[1185] rhFGF Acidic, R&D Systems, cat 232-FA, reconstituted at 100 mg / ml in PBS / 0.1% BSA

[1186] Heparin sodium salt from porcine intestinal mucosa, Sigma Aldrich, cat H3393-100KU, reconstituted to 50 mg / ml in H2O

[1187] ·FGFR3(B-9), Santa Cruz Biotechnology, cat sc-13121

[1188] ECL Anti-Mouse IgG Horseradish Peroxidase Linked Whole Antibody (from sheep) GPR, cat NXA934V,

[1189] ·SuperSignal West Pico PLUS Chemiluminescent Substrate, ThermoScientific, cat 34578,

[1190] ·Cell Lysis Buffer (10x), Cell Signaling Technology, cat 9803.

[1191] ·Phospho-p44 / 42MAPK(Erk1 / 2). Cell Signaling Technology, cat 4370.

[1192] ·p44 / 42MAPK(Erk1 / 2). Cell Signaling Technology, cat 4695.

[1193] Goat anti-rabbit IgG (H+L), HRP-linked antibody. Seracare, catalog number 5450-0010

[1194] For receptor dimerization assays, UMUC14 bladder cancer cells were seeded in complete medium (MEM medium with 10% FBS, 1% non-essential amino acids, Pen / Strep) in 6-well tissue culture plates (Corning) and cultured overnight at 37°C 5% CO2. The cells were then serum starved overnight in starvation medium (MEM medium with 0.5% FBS, Pen / Strep) and then treated with antibodies at specified doses for 3 hours. The cells were washed with pre-cooled PBS and collected in lysis buffer containing protease inhibitors. Equal amounts of cell lysates were analyzed by reducing or non-reducing SDS-PAGE. The blots were blocked in a solution of 0.5% Tween 20 in Tris-buffered saline (TBS) containing 5% skim milk powder and then incubated overnight with an anti-FGFR3 primary antibody (Santa Cruz). After washing three times with TBST and incubating with secondary antibodies, the membranes were developed with SuperSignal West Pico or Femto substrate, and luminescence images were captured with a C300 imager (Azure Biosystems).

[1195] To test the effects of anti-FGFR3 antibodies on ligand-induced signaling, an engineered IL-3-dependent Ba / F3 murine hematopoietic cell line genetically modified to stably express wild-type human fibroblast growth factor receptor 3b was used. Engineered BaF3 / FGFR3b cells were incubated overnight in starvation medium (RPMI1640 + penicillin / streptomycin / L-glutamine + 1 ng / mL mouse IL-3). Following starvation, cells were left untreated or pretreated with 100 nM antibody for 3 hours before stimulation with ligand (human 100 ng / ml FGF1 and 10 mg / ml heparin) for 10 minutes at 37°C. See Figure 3 Cells were lysed in lysis buffer and equal amounts of cell lysates were analyzed by SDS-PAGE. The blots were incubated overnight with pMAPK or MAPK antibodies followed by incubation with anti-rabbit HRP 2 antibodies. The membranes were developed using SuperSignal West Pico or Femto substrates, and luminescent images were captured using a C300 imager (Azure Biosystems).

[1196] Antibody H4H30063P exhibits dose-dependent inhibition of FGFR3 S249C dimerization and stronger inhibition of receptor dimerization than comparator antibody REGN6331. Figure 2 Furthermore, H4H30063P reduced the FGF1 / Hep stimulation-dependent phosphorylation of MAPK. Figure 3 .

[1197] Example 6 : Characterization of FGFR3 antibodies in a cancer cell spheroid proliferation assay using the bladder cancer cell line UMUC14, which carries the endogenous FGFR3 S249C mutation.

[1198] Anti-FGFR3 antibody-mediated inhibition of cancer cell proliferation was evaluated.

[1199] cell lines

[1200] UMUC14 (Sigma-Aldrich): cells were maintained in MEM + 1% non-essential amino acids (NEAA) 10% FBS + P / S; 37°C 5% CO2.

[1201] Reagents

[1202] Corning Spheroid Microplate 96Well, Corning, catalog number 4520

[1203] CellTiter-Glo 3D Cell Viability Assay, Promega, catalog number G9682

[1204] 7500 UMUC14 bladder cancer cells were seeded in culture medium (MEM medium with 10% FBS, 1% non-essential amino acids, Pen / Strep) in a U-bottom low-attachment 96-well spheroid plate (Corning). The cells were cultured at 37°C with 5% CO2 for 48 hours to allow tumor spheroids to form. Tumor spheroids were treated with antibodies with a concentration range of 100nM to 15.2pM in a 1:3 serial dilution, as shown in the figure. The cells were cultured for 5 to 6 days and then the CellTiter-Glo 3D viability assay (Promega) was performed following the manufacturer's protocol. Luminescent signals were read on a SpectraMax M3 microplate reader. Cell proliferation was expressed as a percentage of the untreated control. Data were analyzed using GraphPad Prism software using a three-parameter nonlinear curve fit.

[1205] H4H30063P showed stronger proliferation inhibition than antibody H4H30071P and comparative antibody REGN6331. Figure 4 .

[1206] Example 7 : In vivo characterization of FGFR3 antibodies in a tumor growth inhibition assay using a xenograft model of the bladder cancer cell line UMUC14 carrying the endogenous FGFR3 S249C mutation.

[1207] In this example, inhibition of bladder cancer cell line growth in a mouse xenograft model exposed to anti-FGFR3 antibodies was evaluated.

[1208] cell lines

[1209] UMUC14 (Sigma-Aldrich): cells were maintained in MEM + 1% non-essential amino acids (NEAA) + 10% FBS + P / S; 37°C 5% CO2.

[1210] Reagents

[1211] Matrigel Basement Membrane Matrix. Corning, catalog number 354234, lot number 8085009

[1212] Tumor cells (5×10 6UMUC14 cells in 50% Matrigel (100 μl) were subcutaneously implanted into the right flank of 6- to 8-week-old female SCID mice (Jackson Laboratory). Once tumors were established (volume of approximately 200 mm 3 ), mice were randomly divided into treatment groups (n=10 mice / group) and injected intraperitoneally with anti-FGFR3 antibody or isotype control at 3 mg / kg or 10 mg / kg twice a week. The formula used was: V=0.5xaxb 2 In mm 3 To express tumor volume, a and b are the long and short diameters of the tumor, respectively. All data were analyzed using GraphPad Prism, and tumor size was expressed as mean + SEM to draw.

[1213] In a UMUC14 xenograft model endogenously expressing the FGFR3 S249C mutation, H4H30063P demonstrated enhanced tumor growth inhibition compared to the comparator antibody REGN6331. Figure 5 .

[1214] Example 8 : Effect of FGFR3 oncogenic signaling on CD73 expression.

[1215] The effects of FGFR3 mutations and FGFR3 inhibitors on CD73 expression were evaluated.

[1216] Cell lines:

[1217] UMUC14 (Sigma-Aldrich): cells were maintained in MEM + 1% non-essential amino acids (NEAA) 10% FBS + P / S; 37°C 5% CO2

[1218] Fadu EV and S249C cells were maintained in MEM + 10% FBS + Pen / Strep + 400ug / ml neomycin at 37°C and 5% CO2.

[1219] Reagents:

[1220] FGFR-3 (B-9), Santa Cruz Biotechnology, catalog number sc-13121

[1221] NTSE / CD73 (D7F9A) Rabbit mAb; Cell Signaling Technology. Cat. No. 13160

[1222] Goat anti-rabbit IgG (H+L), HRP conjugated, Seracare, catalog number 5450-0010

[1223] Peroxidase Anti-Mouse IgG (H+L), Vector Laboratories, catalog number PI-2000

[1224] ·SuperSignal West Pico PLUS chemiluminescent substrate, ThermoScientific, catalog number 34578

[1225] SuperSignal West Femto Maximum Substrate, Thermo Scientific, catalog number 34096

[1226] ·Cell Lysis Buffer(10x), Cell Signaling Technology, catalog number 9803

[1227] RIPA buffer, Sigma Aldrich, catalog number R0278

[1228] Matrigel, Corning, catalog number 354234

[1229] To investigate the effects of anti-FGFR3 antibodies or tyrosine kinase inhibitors (AZD4547; commercially available) on CD73 expression, UMUC14 bladder cancer cells were seeded in complete medium (MEM medium with 10% FBS, 1% non-essential amino acids, Pen / Strep) in 6-well tissue culture plates (Corning) and cultured overnight at 37°C 5% CO2. The cells were then treated with antibodies or inhibitors at the indicated concentrations (100 nM, 10 nM, or 1 nM) for 48 hours. The cells were washed with pre-chilled PBS and collected in lysis buffer containing protease and phosphatase inhibitors. Equal amounts of cell lysates were analyzed by SDS-PAGE. The blots were blocked in a solution of 0.5% Tween 20 in Tris-buffered saline (TBS) containing 5% skim milk powder and then incubated overnight with an anti-CD73 primary antibody (Cell Signaling Technology). After washing three times with TBST and incubation with secondary antibodies, the membranes were developed with SuperSignal West Pico or Femto substrate, and luminescence images were captured with a C300 imager (Azure Biosystems).

[1230] To test the effect of FGFR3 oncogenic signaling on CD73 expression in vivo, 3 × 10 6 Fadu cells expressing FGFR3 oncogenic mutations (S249C or FGFR3-TACC3) or empty mediator control (EV) were subcutaneously implanted into the right flank of 6- to 8-week-old female SCID mice (Jackson Laboratory). Approximately 16 days after implantation, tumors were harvested, snap-frozen, and lysed in RIPA buffer. Equal amounts of tumor lysates were analyzed by SDS-PAGE and blotted with anti-CD73 and anti-FGFR3 antibodies as described above.

[1231] To test the effect of anti-FGFR3 inhibitory antibodies or tyrosine kinase inhibitor (AZD4547) on CD73 expression in vivo, tumor cells (5 × 10 6 UMUC14, 3×10 6 Fadu EV or S249C in 50% Matrigel) were implanted subcutaneously into the right flank of 6- to 8-week-old female SCID mice (Jackson Laboratory). Once tumors were established (volume of approximately 200 mm 3 ), mice were randomly divided into treatment groups (n=5 to 6 mice / group) and injected intraperitoneally with anti-FGFR3 antibody (15 mg / kg) or isotype control. Tyrosine kinase inhibitor AZD4547 (25 mg / kg) was administered by gavage once daily for 3 days. Tumors were collected 4 days after the start of treatment. Tumors were collected, quickly frozen and lysed in RIPA buffer. Equal amounts of tumor lysates were analyzed by SDS-PAGE and blotted with anti-CD73 and anti-FGFR3 antibodies as described above. The membranes were developed with SuperSignal West Pico or Femto substrates, and luminescent images were captured with a C300 imager (Azure Biosystems). Image J (NIH) was used to quantify the intensity of each CD73 and actin band, and Prism Graphpad was used to plot the CD73 / actin ratio for each sample.

[1232] Downregulation of CD73 protein levels in response to FGFR3 inhibition in UMUC14 cells in vitro. Figure 6 As shown in , both anti-FGFR3 inhibitory antibodies and pan-FGFR tyrosine kinase inhibitors (AZD4547) showed dose-dependent downregulation of CD73 expression. As the molar concentration of each agent increased from 1 nM to 100 nM, the CD73 band intensity on the blot decreased.

[1233] Downregulation of CD73 protein levels in response to FGFR3 inhibition in UMUC14 cells in vivo. The CD73 band intensity decreased with increasing concentrations of anti-FGFR3 antibody in the blot. Figure 7 . Figure 8 The band intensities of CD73 / actin are summarized graphically in .

[1234] FGFR3 activation is sufficient to induce CD73 expression. Figure 9 As shown in the blot of , cells expressing constitutively active FGFR3 mutants (without ligand-induced activation) in vitro exhibited increased CD73 expression relative to control and wild-type FGFR3.

[1235] Upregulation of CD73 expression in Fadu tumors engineered to express the FGFR3 S249C mutant or the FGFR3-TACC3 fusion. Empty mediator (EV; Figure 10 (A) CD73 expression in Fadu tumors showed little or no activation of CD73 expression, whereas those expressing S249C ( Figure 10 (B)) or FGFR-TACC3( Figure 10 (C) FGFR3 mutant tumors exhibit increased CD73 expression.

[1236] Downregulation of CD73 protein levels in response to FGFR3 inhibition in Fadu S249C tumors in vivo. Mice bearing FADU tumors expressing the FGFR3 S249C mutant treated with a single intraperitoneal dose of FGFR3 mAb (15 mg / kg) or daily gavage of AZD4547 (25 mg / kg) exhibited reduced CD73 expression relative to control-treated mice. Figure 11 (B) Figure 11 CD73 band intensity in the blot shown in (A) was quantified.

[1237] Example 9 : Antibody inhibition of proliferation of BaF3 cells expressing TKI resistance mutations.

[1238] BaF3 cells, an IL-3-dependent murine pre-B cell line, were engineered to stably express full-length human FGFR3b S249C, V557L, V557M, S249C / V557L, S249C / V557M (WT FGFR3b accession number NP_001156685.1, amino acid sequence M1-T808). Cells were maintained in RPMI 1640 + 10% FBS + P / S / G + 1 ng / ml mouse IL-3 + 500 ug / ml neomycin at 37°C with 5% CO2. For proliferation assays, cells were washed with IL-3-free medium and incubated for 10 min.5 Cells / well were seeded in 96-well black-walled tissue culture plates. Cells were treated with 1:3 serial dilutions of antibodies as indicated in the presence or absence of 5 μg / ml heparin and 1 nM human FGF1. After addition of antibodies, cells were incubated at 37°C / 5% CO2 for 72 h, after which an equal volume of CellTiter-Glo was added. TM Cells were lysed with luciferase activity assayed using luciferase reagent (Promega). Luminescence signals were quantified using an Envision microplate reader (PerkinElmer). EC50 values of the antibodies were determined using GraphPad Prism software.

[1239] Acquired resistance to FGFR TKIs has been reported and is often associated with secondary mutations in the kinase domain (Facchinetti F et al. AACR 2023, Abstract 3458, Chell V et al. Oncogene 2013). One of the hotspots of resistance mutations that appears to drive disease progression is the gatekeeper mutation V555M / L. To test the efficacy of FGFR3 antibodies in the context of TKI resistance mutations, BaF3 cell lines expressing FGFR3 S249C (with or without the gatekeeper mutations V557M or V557L) were generated. The pan-FGFR TKIs AZD4547 and erdafitinib potently inhibited the growth of BaF3 cells expressing FGFR3 S249C (IC50 of 9.9 nM and 1.2 nM, respectively), but were ineffective in cells expressing FGFR3 containing only the V557M / L mutation or both the S249C and V557M / L mutations. In contrast, the FGFR3 antibody H4H30063P was able to strongly inhibit the growth of BaF3 cells expressing double mutant FGFR3 (S249C plus V557M or L). The IC50 values of H4H30063P against S249C, S249C / V557M, and S249C / V557L were 1.36 nM, 3.9 nM, and 4.3 nM, respectively. See Figure 12.

[1240] Example 10 : Hydrogen / deuterium exchange (HDX) epitope mapping.

[1241] HDX experiments were performed using a custom HDX automation system (NovaBioAssays, MA) coupled to a Q Exactive HF mass spectrometer (Thermo Fisher Scientific, MA). Figure 21 An exemplary HDX mass spectrometry experimental procedure is shown.

[1242] To start deuterium exchange, 10 μL of protein sample (hFGFR3b.mmh alone, or hFGFR3b.mmh and H4H30117P2, H4H30063P, H4H30045P or H4H30108P2 mixed in a 2:1 ratio) was diluted with 90 μL PBS-D2O buffer (10 mM, pH 7.4 at 25°C). After 5 or 10 minutes, deuterium exchange was quenched by adding 100 μL quenching buffer (0.5 M TCEP, 4 M guanidine hydrochloride, pH 2.08), followed by incubation for 90 seconds at 20°C. The quenched sample was digested with 100 μL / min 0.1% formic acid aqueous solution at room temperature through an online pepsin / protease XIII column (NovaBioAssays, Massachusetts). The digestive peptides were captured by an ACQUITY UPLC Peptide BEH C18 VanGuard Pre-column (2.0 x 5 mm, Waters, Massachusetts) and further separated by a 15-minute gradient using 200 μL / min of 0.1% formic acid in water and 0.1% formic acid in acetonitrile as the mobile phase over an ACQUITY UPLC Peptide BEH C18 column (2.0 x 50 mm, Waters, Massachusetts) at -5° C. The eluted peptides were analyzed by a Q Exactive HF mass spectrometer in LC-MS / MS or LC-MS mode.

[1243] The percentage of deuterium uptake (D%) was calculated for each peptide. The difference in deuterium uptake was calculated as ΔD% = D% of hFGFR3b antibody - D% of hFGFR3b. Differences were considered significant if |ΔD| > 5% (average of 2 replicates). The mass spectra of peptides showing significant differences were manually confirmed.

[1244] The results of HDX epitope mapping for anti-FGFR3b antibodies H4H30117P2 and H4H30063P are Figure 13 The results of HDX epitope mapping for anti-FGFR3b antibodies H4H30045P and H4H30108P2 are shown in Figure 14 Shown in. Figure 15 HDX protection of FGFR3 by anti-FGFR3b antibodies H4H30063P Fab and H4H30117P2 scFv is shown in Figure 16 . The HDX epitope mapping of FGFR3 antibodies is shown in Figure 16 (A to B). As shown in the structure, the epitope comprises segments of peptide that form a continuous surface patch for interaction. The epitope is likely a conformational epitope.

[1245] The results of HDX epitope mapping for H4H30063P are Figure 17The results of HDX epitope mapping for H4H30108P2 are shown in Figure 18 The results of HDX epitope mapping for H4H30117P2 are shown in Figure 19 The results of HDX epitope mapping for H4H30045P are shown in Figure 20 Shown in.

[1246] *****

[1247] All references cited herein are incorporated by reference, and their degree is as each independent publication, database entry (for example, Genbank sequence or GeneID entry), patent application or patent is specially and individually indicated to be incorporated by reference. The applicant wishes that the statement incorporated by reference is relevant to each independent publication, database entry (for example, Genbank sequence or GeneID entry), patent application or patent, even if this type of quoting is not next to the special statement incorporated by reference, each document in these documents is also clearly indicated. In the specification sheet, comprising the special statement incorporated by reference (if any) will never weaken the general statement incorporated by reference in any way. This paper is not intended to admit that this reference is the relevant prior art to the quoting of the reference, nor does it constitute any recognition of the content or date of these publications or files.

Claims

1. An isolated antibody or antigen-binding fragment thereof that specifically binds to FGFR3 or an antigenic fragment thereof, the isolated antibody or antigen-binding fragment thereof comprising: a heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of a HCVR comprising the amino acid sequence set forth in SEQ ID NO: 2, 22, 42, 62, 82, 102, 122, 140, 159, 169, 179, 199, or 219, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of a LCVR comprising the amino acid sequence set forth in SEQ ID NO: 10, 30, 50, 70, 90, 110, 130, 148, 187, 207, or 227.

2. An isolated antibody or antigen-binding fragment thereof that specifically binds to FGFR3 or an antigenic fragment thereof, the isolated antibody or antigen-binding fragment thereof comprising: (a) a heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of the HCVR comprising the amino acid sequence set forth in SEQ ID NO: 2, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of the LCVR comprising the amino acid sequence set forth in SEQ ID NO: 10, (b) a heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of a HCVR comprising the amino acid sequence set forth in SEQ ID NO: 22, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of a LCVR comprising the amino acid sequence set forth in SEQ ID NO: 30, (c) a heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of a HCVR comprising the amino acid sequence set forth in SEQ ID NO:42, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of a LCVR comprising the amino acid sequence set forth in SEQ ID NO:50, (d) a heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of a HCVR comprising the amino acid sequence set forth in SEQ ID NO: 62, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of a LCVR comprising the amino acid sequence set forth in SEQ ID NO: 70, (e) a heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of a HCVR comprising the amino acid sequence set forth in SEQ ID NO:82, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of a LCVR comprising the amino acid sequence set forth in SEQ ID NO:90, (f) a heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of a HCVR comprising the amino acid sequence set forth in SEQ ID NO: 102, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of a LCVR comprising the amino acid sequence set forth in SEQ ID NO: 110, (g) a heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of a HCVR comprising the amino acid sequence set forth in SEQ ID NO: 122, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of a LCVR comprising the amino acid sequence set forth in SEQ ID NO: 130, (h) a heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of a HCVR comprising the amino acid sequence set forth in SEQ ID NO: 140, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of a LCVR comprising the amino acid sequence set forth in SEQ ID NO: 148, (i) a heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of a HCVR comprising the amino acid sequence set forth in SEQ ID NO: 159, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of a LCVR comprising the amino acid sequence set forth in SEQ ID NO: 148, (j) a heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of a HCVR comprising the amino acid sequence set forth in SEQ ID NO: 169, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of a LCVR comprising the amino acid sequence set forth in SEQ ID NO: 148, (k) a heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of a HCVR comprising the amino acid sequence set forth in SEQ ID NO: 179, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of a LCVR comprising the amino acid sequence set forth in SEQ ID NO: 187, (1) a heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of a HCVR comprising the amino acid sequence set forth in SEQ ID NO: 199, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of a LCVR comprising the amino acid sequence set forth in SEQ ID NO: 207, and / or (m) a heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of the HCVR comprising the amino acid sequence set forth in SEQ ID NO: 219, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of the LCVR comprising the amino acid sequence set forth in SEQ ID NO:

227.

3. An isolated antibody or antigen-binding fragment thereof that specifically binds to FGFR3 or an antigenic fragment thereof, the isolated antibody or antigen-binding fragment thereof comprising: (a) a heavy chain variable region comprising: a HCDR1 comprising the amino acid sequence set forth in SEQ ID NO:4, a HCDR2 comprising the amino acid sequence set forth in SEQ ID NO:6, and a HCDR3 comprising the amino acid sequence set forth in SEQ ID NO:8, and a light chain variable region comprising: a LCDR1 comprising the amino acid sequence set forth in SEQ ID NO:12, a LCDR2 comprising the amino acid sequence set forth in SEQ ID NO:14, and a LCDR3 comprising the amino acid sequence set forth in SEQ ID NO:16; (b) a heavy chain variable region comprising: a HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 24, a HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 26, and a HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 28, and a light chain variable region comprising: a LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 32, a LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 34, and a LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 36; (c) a heavy chain variable region comprising: a HCDR1 comprising the amino acid sequence set forth in SEQ ID NO:44, a HCDR2 comprising the amino acid sequence set forth in SEQ ID NO:46, and a HCDR3 comprising the amino acid sequence set forth in SEQ ID NO:48, and a light chain variable region comprising: a LCDR1 comprising the amino acid sequence set forth in SEQ ID NO:52, a LCDR2 comprising the amino acid sequence set forth in SEQ ID NO:54, and a LCDR3 comprising the amino acid sequence set forth in SEQ ID NO:56; (d) a heavy chain variable region comprising: a HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 64, a HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 66, and a HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 68, and a light chain variable region comprising: a LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 72, a LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 74, and a LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 76; (e) a heavy chain variable region comprising: a HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 84, a HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 86, and a HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 88, and a light chain variable region comprising: a LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 92, a LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 94, and a LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 96; (f) a heavy chain variable region comprising: a HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 104, a HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 106, and a HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 108, and a light chain variable region comprising: a LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 112, a LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 114, and a LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 116, (g) a heavy chain variable region comprising: a HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 124, a HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 126, and a HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 128, and a light chain variable region comprising: a LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 132, a LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 34, and a LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 134; (h) a heavy chain variable region comprising: a HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 142, a HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 144, and a HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 146, and a light chain variable region comprising: a LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 150, a LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 153; (i) a heavy chain variable region comprising: a HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 161, a HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 163, and a HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 165, and a light chain variable region comprising: a LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 150, a LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 153; (j) a heavy chain variable region comprising: a HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 171, a HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 173, and a HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 175, and a light chain variable region comprising: a LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 150, a LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 14, and a LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 153; (k) a heavy chain variable region comprising: a HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 181, a HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 183, and a HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 185, and a light chain variable region comprising: a LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 189, a LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 191, and a LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 193; (1) a heavy chain variable region comprising: a HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 201, a HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 203, and a HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 205, and a light chain variable region comprising: a LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 209, a LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 211, and a LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 213; and / or (m) a heavy chain variable region comprising a HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 221, a HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 223, and a HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 225, and a light chain variable region comprising a LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 32, a LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 34, and a LCDR3 comprising the amino acid sequence set forth in SEQ ID NO:

76.

4. An isolated antibody or antigen-binding fragment thereof that specifically binds to FGFR3 or an antigenic fragment thereof, the isolated antibody or antigen-binding fragment thereof comprising: a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 2, 22, 42, 62, 82, 102, 122, 140, 159, 169, 179, 199 or 219, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 10, 30, 50, 70, 90, 110, 130, 148, 187, 207 or 227.

5. An isolated antibody or antigen-binding fragment thereof that specifically binds to FGFR3 or an antigenic fragment thereof, the isolated antibody or antigen-binding fragment thereof comprising: (a) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 2, and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 10; (b) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 22, and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: A light chain variable region having the amino acid sequence set forth in 30; (c) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 42, and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: A light chain variable region having the amino acid sequence set forth in 50; (d) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 62, and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: A light chain variable region having the amino acid sequence set forth in 70; (e) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 82, and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: A light chain variable region having the amino acid sequence set forth in 90; (f) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 102, and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: a light chain variable region having the amino acid sequence set forth in 110; (g) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 122, and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: a light chain variable region having the amino acid sequence set forth in 130; (h) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 140, and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: a light chain variable region having the amino acid sequence set forth in 148; (i) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 159, and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: a light chain variable region having the amino acid sequence set forth in 148; (j) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 169, and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: a light chain variable region having the amino acid sequence set forth in 148; (k) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 179, and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: a light chain variable region having the amino acid sequence set forth in 187; (1) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 199, and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: a light chain variable region having the amino acid sequence set forth in 207; and / or (m) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 219, and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: The light chain variable region has the amino acid sequence set forth in 227.

6. An isolated antibody or antigen-binding fragment thereof that specifically binds to FGFR3 or an antigenic fragment thereof, the isolated antibody or antigen-binding fragment thereof comprising: (a) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 18, 38, 58, 78, 98, 118, 136, 155, 167, 177, 195, 215 or 229, and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 20, 40, 60, 80, 100, 120, 138, 157, 197, 217 or 231.

7. An isolated antibody or antigen-binding fragment thereof that specifically binds to FGFR3 or an antigenic fragment thereof, the isolated antibody or antigen-binding fragment thereof comprising: (a) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 18, and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 20; (b) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:38, and a light chain comprising the amino acid sequence set forth in SEQ ID NO:40; (c) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 58, and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 60; (d) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 78, and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 80; (e) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 98, and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 100; (f) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 118, and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 120; (g) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 136, and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 138; (h) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 155, and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 157; (i) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 167, and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 157; (j) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 177, and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 157; (k) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 195, and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 197; (1) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 215, and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 217; and / or (m) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 229, and a light chain comprising the amino acid sequence set forth in SEQ ID NO:

231.

8. An isolated antibody or antigen-binding fragment thereof that specifically binds to FGFR3 or an antigenic fragment thereof, wherein the antibody or antigen-binding fragment binds to the same FGFR3 epitope as the antibody or antigen-binding fragment according to any one of claims 1 to 7, or competes with the antibody or antigen-binding fragment for binding to FGFR3.

9. An isolated antibody or antigen-binding fragment thereof that specifically binds to FGFR3 or an antigenic fragment thereof, wherein the antibody or antigen-binding fragment thereof binds to one or more FGFR3 epitopes selected from the group consisting of: a. an epitope comprising the sequence GPTVWVK (SEQ ID NO: 260), and / or an epitope comprising the sequence TQR; b. an epitope comprising the sequence ADVR (SEQ ID NO: 258), and / or an epitope comprising the sequence IGVAEK (SEQ ID NO: 259) epitope; c. an epitope comprising the sequence HCKVY (SEQ ID NO: 261), and / or an epitope comprising the sequence KSWISE (SEQ ID NO: 262), and / or an epitope comprising the sequence ADVR (SEQ ID NO: 258); d. an epitope contained within or overlapping with the sequence GPTVWVK (SEQ ID NO: 260), and / or epitopes contained within or overlapping with: sequence TQR; e. an epitope contained within or overlapping with the sequence ADVR (SEQ ID NO: 258), and / or an epitope contained within or overlapping with the sequence IGVAEK (SEQ ID NO: 259); and f. An epitope contained within or overlapping with the sequence HCKVY (SEQ ID NO: 261), and / or an epitope contained within or overlapping with the sequence KSWISE (SEQ ID NO: 262), and / or an epitope contained within or overlapping with the sequence ADVR (SEQ ID NO: 258).

10. The antibody or antigen-binding fragment of claim 9, wherein the antibody or antigen-binding fragment thereof binds to one or more FGFR3 epitopes selected from the group consisting of: a. an epitope consisting of the sequence GPTVWVK (SEQ ID NO: 260), and / or an epitope consisting of the sequence TQR; b. An epitope consisting of the sequence ADVR (SEQ ID NO: 258), and / or an epitope consisting of the sequence IGVAEK (SEQ ID NO: 259); and c. An epitope consisting of the sequence HCKVY (SEQ ID NO: 261), and / or an epitope consisting of the sequence KSWISE (SEQ ID NO: 262), and / or an epitope consisting of the sequence ADVR (SEQ ID NO: 258).

11. An isolated antibody or antigen-binding fragment thereof that specifically binds to FGFR3 or an antigenic fragment thereof, wherein the antibody or antigen-binding fragment thereof binds to one or more FGFR3 epitopes selected from the group consisting of: a. an epitope comprising the sequence SCPPPGGGPMGPTVWVKDGTGLVPSER (SEQ ID NO: 245), and / or an epitope comprising the sequence YSCRQRLTQRVL (SEQ ID NO: 246); b. an epitope comprising the sequence LLAVPAAN (SEQ ID NO: 247), and / or an epitope comprising the sequence VLERSPHRPILQAG (SEQ ID NO: 248), and / or an epitope comprising the sequence YVTVLKSWISE (SEQ ID NO: 249), and / or an epitope comprising the sequence ADVRLR (SEQ ID NO: 250), and / or an epitope comprising the sequence LCRATNFIGVAEKAFW (SEQ ID NO: 251); c. an epitope comprising the sequence GQQEQLVFGSGDAVE (SEQ ID NO: 252), and / or an epitope comprising the sequence VLVGPQRL (SEQ ID NO: 253); d. an epitope comprising the sequence VLERSPHRPILQAG (SEQ ID NO: 254), and / or an epitope comprising the sequence HCKVYSDAQP (SEQ ID NO: 255), and / or an epitope comprising the sequence YVTVLKSWISESVEADVRLR (SEQ ID NO: 256), and / or an epitope comprising the sequence LCRATNFIGVAEKAF (SEQ ID NO: 257); e. An epitope contained within or overlapping with the sequence SCPPPGGGPMGPTVWVKDGTGLVPSER (SEQ ID NO: 245), and / or an epitope contained within or overlapping with the sequence YSCRQRLTQRVL (SEQ ID NO: 246); f. An epitope contained within or overlapping with the sequence LLAVPAAN (SEQ ID NO: 247), and / or an epitope contained within or overlapping with the sequence VLERSPHRPILQAG (SEQ ID NO: 248), and / or an epitope contained within or overlapping with the sequence YVTVLKSWISE (SEQ ID NO: 249), and / or or an epitope contained within or overlapping with the sequence ADVRLR (SEQ ID NO: 250), and / or an epitope contained within or overlapping with the sequence LCRATNFIGVAEKAFW (SEQ ID NO: 251); g. an epitope contained within or overlapping with the sequence GQQEQLVFGSGDAVE (SEQ ID NO: 252), and / or an epitope contained within or overlapping with the sequence VLVGPQRL (SEQ ID NO: 253); and h. An epitope contained within or overlapping with the sequence VLERSPHRPILQAG (SEQ ID NO: 254), and / or an epitope contained within or overlapping with the sequence HCKVYSDAQP (SEQ ID NO: 255), and / or an epitope contained within or overlapping with the sequence YVTVLKSWISESVEADVRLR (SEQ ID NO: 256), and / or an epitope contained within or overlapping with the sequence LCRATNFIGVAEKAF (SEQ ID NO: 257).

12. The antibody or antigen-binding fragment of claim 11, wherein the antibody or antigen-binding fragment thereof binds to one or more FGFR3 epitopes selected from the group consisting of: a. an epitope consisting of the sequence SCPPPGGGPMGPTVWVKDGTGLVPSER (SEQ ID NO: 245), and / or an epitope consisting of the sequence YSCRQRLTQRVL (SEQ ID NO: 246); b. an epitope consisting of the sequence LLAVPAAN (SEQ ID NO: 247), and / or an epitope consisting of the sequence VLERSPHRPILQAG (SEQ ID NO: 248), and / or an epitope consisting of the sequence YVTVLKSWISE (SEQ ID NO: 249), and / or an epitope consisting of the sequence ADVRLR (SEQ ID NO: 250), and / or an epitope consisting of the sequence LCRATNFIGVAEKAFW (SEQ ID NO: 251); c. an epitope consisting of the sequence GQQEQLVFGSGDAVE (SEQ ID NO: 252), and / or an epitope consisting of the sequence VLVGPQRL (SEQ ID NO: 253); and d. An epitope consisting of the sequence VLERSPHRPILQAG (SEQ ID NO: 254), and / or an epitope consisting of the sequence HCKVYSDAQP (SEQ ID NO: 255), and / or an epitope consisting of the sequence YVTVLKSWISESVEADVRLR (SEQ ID NO: 256), and / or an epitope consisting of the sequence LCRATNFIGVAEKAF (SEQ ID NO: 257).

13. The antibody or antigen-binding fragment of any one of claims 1 to 12, wherein FGFR3 is monomeric or dimeric FGFR3b.

14. An isolated antibody or antigen-binding fragment thereof that specifically binds to FGFR3 or an antigenic fragment thereof, wherein the isolated antibody or antigen-binding fragment thereof is characterized by one or more of the following: At 25°C, it binds with an affinity of approximately 16 nM in a surface plasmon resonance assay (K D ) or greater affinity to monomeric human FGFR3b tagged with myc-myc-His6 at the C-terminus; At 25°C with an affinity of approximately 20 nM in a surface plasmon resonance assay (K D ) or greater affinity to monomeric cynomolgus monkey FGFR3b tagged at the C-terminus with myc-myc-His6; At 25°C, it binds with an affinity of approximately 70 nM in a surface plasmon resonance assay (K D ) or greater affinity to monomeric murine FGFR3b tagged with myc-myc-His6 at the C-terminus; Does not significantly bind to monomeric human FGFR3c tagged at the C-terminus with myc-myc-His6 in a surface plasmon resonance assay at 25°C; binds to dimeric human FGFR3b tagged at the C-terminus with a mouse Fc at 25°C with an affinity of about 0.6 nM or greater in a surface plasmon resonance assay; Blocks the binding of FGF1 acid to human FGFR3b-mFc by approximately 68% or more at 200 nM of the antibody. The K values for binding to monomeric or dimeric human FGFR3b were determined in a surface plasmon resonance assay at 25°C. D K values vary by about 0.1 nM D Binds to monomeric cynomolgus monkey and monomeric mouse FGFR3b; With an IC of approximately 15 nM 50 or lower concentrations to block the binding of 4 nM human FGFR3b-mFc to human FGF1 acidic protein; With an IC of approximately 18 nM 50 or lower concentrations to block intracellular signaling in an engineered IL-3-dependent Ba / F3 murine hematopoietic cell line genetically modified to stably express wild-type or S249C mutant human fibroblast growth factor receptor 3b, which has been stimulated with about 5 micrograms / ml of human heparin and about 1 nM of human FGF1 ligand; · Lower than the following IC 50 Blocking intracellular signaling in an engineered IL-3-dependent Ba / F3 murine hematopoietic cell line that has been genetically modified to stably express S249C mutant human fibroblast growth factor receptor 3b and has been stimulated with about 5 micrograms / ml of human heparin and about 1 nM of human FGF1 ligand: Blocking intracellular signaling in an engineered IL-3-dependent Ba / F3 murine hematopoietic cell line that has been genetically modified to stably express wild-type human fibroblast growth factor receptor 3b and has been stimulated with about 1 nM of human FGF1 ligand and about 5 micrograms / ml of human heparin; Blocks dimerization of FGFR3 or its S249C mutant with stronger inhibition than that of REGN6331 as measured in a non-reducing SDS-PAGE assay; reducing the tumor size of a bladder cancer tumor expressing FGFR3 or its S249C mutant in a subject to which the antibody or fragment is administered; reducing CD73 expression in bladder cancer tumors expressing FGFR3 or the S249C mutant thereof in a subject to which the antibody or fragment is administered; Inhibits FGF1 / heparin-induced MAPK phosphorylation in BaF3 cells expressing wild-type FGFR3 or its S249C mutant. Inhibits the proliferation of UMUC14 bladder cancer cells expressing endogenous FGFR3 or its S249C mutation in a cancer cell spheroid proliferation assay; Inhibits tumor growth in a SCID mouse xenograft model of the bladder cancer cell line UMUC14 expressing FGFR3 or its S249C mutation; Inhibits CD73-dependent adenosine-mediated suppression of immune cell activation; Increase the CD8 / CD4 and / or CD8+ / T in tumor tissues with tumor cells expressing FGFR3 or its S249C mutant reg ratio; Inhibit FGF3-mediated activation of CD73 expression and / or adenosine production on tumor cells expressing FGFR3 or its S249C mutant; Inhibit FGFR3-dependent adenosine-mediated suppression of immune cells; or Inhibits the growth of BaF3 cells expressing the FGFR3 double mutants S249C and V557M or S249C and V557L. 15 . A complex comprising the antibody or antigen-binding fragment thereof according to claim 1 , which binds to FGFR3 or an antigenic fragment thereof.

16. A pharmaceutical formulation comprising the antibody or antigen-binding fragment according to any one of claims 1 to 14, and a pharmaceutically acceptable carrier.

17. An isolated polypeptide comprising an amino acid sequence selected from the group consisting of: SEQ ID NO: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, 94, 96, 98, 100, 102, 104, 106, 108, 110, 112, 114, 116, 118, 120, 122, 124, 126, 128 , 130, 132, 134, 136, 138, 140, 142, 144, 146, 148, 150, 153, 155, 157, 159, 161, 163, 165, 167, 169, 171, 173, 175, 177, 179, 181, 183, 185, 187, 189, 191, 193, 195, 197, 199, 201, 203, 205, 207, 209, 211, 213, 215, 217, 219, 221, 223, 225, 227, 229 and 231.

18. An isolated polynucleotide encoding any one or more of the polypeptides according to claim 17.

19. The polynucleotide of claim 18, comprising a nucleotide sequence selected from the group consisting of: SEQ ID NO: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 59, 61, 63, 65, 67, 69, 71, 73, 75, 77, 79, 81, 83, 85, 87, 89, 91, 93, 95, 97, 99, 101, 103, 105, 107, 109, 111, 113, 115, 117, 119, 121, 123, 125, 127, 9, 131, 133, 135, 137, 139, 141, 143, 145, 147, 149, 151, 152, 154, 156, 158, 160, 162, 164, 166, 168, 170, 172, 174, 176, 178, 180, 182, 184, 186, 188, 190, 192, 194, 196, 198, 200, 202, 204, 206, 208, 210, 212, 214, 216, 218, 220, 222, 224, 226, 228 and 230.

20. A mediator comprising the polynucleotide according to any one of claims 18 to 19.

21. A host cell comprising the polynucleotide according to any one of claims 18 to 19.

22. A method for preparing the antibody or antigen-binding fragment according to any one of claims 1 to 14, the method comprising: A polynucleotide encoding the chain of the antibody or antigen-binding fragment is introduced into a host cell, and the host cell containing the polynucleotide is incubated in a culture medium under conditions conducive to the expression of the chain, and the antibody or antigen-binding fragment is optionally isolated from the host cell and / or culture medium.

23. A method for administering to a subject the antibody or antigen-binding fragment of any one of claims 1 to 14, the method comprising: The antibody or antigen-binding fragment is introduced into the subject.

24. The method of claim 23, wherein the antibody or antigen-binding fragment is introduced into the body by injection.

25. The method of claim 24, wherein the injection is intramuscular, intravenous, or subcutaneous.

26. A method for treating or preventing an FGFR3-mediated disorder in a subject in need thereof, the method comprising: A therapeutically effective amount of the antibody or antigen-binding fragment of any one of claims 1 to 14 is administered to the subject.

27. The method of claim 26, wherein the FGFR3-mediated disorder is cancer, bladder cancer, brain cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, gastric cancer, head and neck cancer, kidney cancer, lung cancer, multiple myeloma, ovarian cancer, pancreatic cancer, urothelial cancer, achondroplasia, Crouzon syndrome with acanthosis nigricans, epidermal nevus, hypochondroma; lacrimal-auricular-dental-digital (LADD) syndrome, muenke syndrome, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), and / or thanatophoric dysplasia.

28. The method of any one of claims 23 to 27, wherein the subject is administered an additional therapeutic agent.

29. The method of claim 28, wherein the additional therapeutic agent is one or more selected from the group consisting of: an FGFR inhibitor, erdafitinib, pemitinib, infigratinib, rogatinib, dexamethasone, an alkylating agent, altretinoin, trabectedin or busulfan, a nitrosourea, carmustine, lomustine, a cytotoxic antibiotic, an anthracycline, doxorubicin, valrubicin, bleomycin or dactinomycin, an antimetabolite, methotrexate, floxuridine, clofarabine, pralatrexate, Vinca alkaloids, vinblastine, vinorelbine, vincristine, vindesine, photodynamic drugs, porfimer sodium, aminolevulinic acid, platinum drugs, cisplatin, phenanthriplatin, taxanes, paclitaxel, docetaxel, topoisomerase inhibitors, irinotecan, topotecan, etoposide, teniposide, ziv-aflibercept, anticancer antibodies, rituximab, trastuzumab, cetuximab, cemiplizumab, pembrolizumab, panitumumab, and bevacizumab.

30. A method for in vivo administration of: - Reduce the metastasis of tumor cells expressing FGFR3, - reducing adenosine concentrations in FGFR3-expressing tumors, - Reduced CD73-dependent catalysis of AMP to adenosine by FGFR3-expressing tumors, - Inhibits adenosine-mediated suppression of T cell function in FGFR3-expressing tumors, The method comprises: A therapeutically effective amount of the antibody or antigen-binding fragment of any one of claims 1 to 14 is administered to the subject.

31. The method of claim 30, wherein the transfer is CD73-dependent or adenosine-dependent.

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